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rsc.li/obc

Organic &

Biomolecular

Chemistry

www.rsc.org/obc

ISSN 1477-0520

COMMUNICATION

Takeharu Haino et al.

Solvent-induced emission of organogels based on tris(phenylisoxazolyl)

benzene

Volume 14 Number 1 7 January 2016 Pages 1–372

Organic &

Biomolecular

Chemistry

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Dorta, S. Jana, L. Borkova, J. Thomas and W. Dehaen, Org. Biomol. Chem., 2018, DOI:

10.1039/C8OB00533H.

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Accepted 00th January 20xx

DOI: 10.1039/x0xx00000x

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Straightforward synthesis of enantiomerically pure 1,2,3-triazoles

derived from amino esters

Gaston Silveira-Dorta,

a

Sampad Jana,

a

Lucie Borkova,

b

Joice Thomas

a

and Wim Dehaen

*

a

A practical and strightforward approach that enables for the first time, the synthesis of enantiomerically pure 1,4,5-

trisubstituted, 1,5-disubstituted, and fused 1,2,3 triazoles derivatives has been developed. The synthesis employs

enantiomerically pure amino esters derived from amino acids and commercially available ketones under metla-free

conditons.

Introduction

Amino acids represent a valuable enantiomerically pure source

in organic chemistry, being widely employed as chiral starting

materials for the synthesis of peptides

1a

and more complex

structures,

2b

with broad biomedical implications.

1c,d

In the last

decades, the 1,2,3-triazole scaffold has received great

attention from the scientist, due to its feasible synthesis and

compatibility with diverse substrates.

2a

In addition, triazoles

play a crucial role in the drug discovery process owing to the

ability of 1,2,3-triazole to mimic amide and ester groups which

allows the expansion of the chemical space towards the

synthesis of diverse triazole bioisosteres.

2b

In the literature,

most of the work reported to access the 1,4- and 1,5-

disubstituted 1,2,3-triazole moiety has relied on Cu-

3a

and Ru-

catalyzed

3b

azide-alkyne cycloaddition reactions respectively.

Recently, the combination of amino acids and 1,5-di- and

1,4,5-trisubstituted triazoles has emerged as a powerful

strategy to combat several diseases, for instance, apicidin

analogues (

1a

),

4a

glutamate analogues (

1b

)

4b

and

histone/protein deacetylase 8 inhibitors

(

2

) (Fig. 1).

4c

Despite

of these exceptional results, the metal toxicity and side effects

in biological systems produced by Cu and Ru are well known.

As a consequence, such procedures have not been

recommended in drug research programs.

5

In this regard,

metal free approaches towards 1,2,3-triazoles have emerged

as a new alternative.

6

Although metals are avoided, earlier

methodologies relying on 1,3-dipolar cycloadditions have not

been further used due to (i) the generation of regioisomeric

mixtures, (ii) the limited scope and (iii) the multistep reaction

sequences required for the synthesis of the starting materials.

Recently, the metal free organocatalytic synthesis of 1,2,3-

triazoles

7

has allowed a straightforward and highly

regioselective manner to access diversely functionalized 1,2,3-

triazoles, inaccessible by other means. Moreover, this

methodology uses cheap and readily available building blocks,

attractive advantages in the field of drug design.

8

Lately, our

group has reported a very general multicomponent

triazolization strategy that can be applied to the synthesis of

1,4,5-trisubstituted, 1,5-disubstituted and 1,5-fused 1,2,3-

triazoles.

9

This method relies on using commercially available

enolizable ketones, primary amines and p-nitrophenyl azide

(PNA) as a dinitrogen source.

Then, this method was

successfully applied to obtain potential anti-HIV compounds

derived from dihydroartemisinin.

10

Building further on our

previous work and driven by our interest in drug search, in this

paper we describe for the first time the synthesis of

enantiomerically pure 1,2,3-triazole derivatives of amino acids,

using commercially available ketones and amino esters derived

from natural amino acids.

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Results and discussion

Initially, we started with the synthesis of 4,5- fused tri-substituted

1,2,3-triazoles. To achieve our goal, we used a reaction mixture

composed of 5α-cholestan-3-one (3),

L

-phenylalanine tert-butyl

ester (4a), PNA and acetic acid (AcOH) as a catalyst in anhydrous

toluene at 100 °C for 24 h

9a

(Entry 1, Table 1). It is important to

mention that 3 was selected as a model reagent to easily detect any

racemization which could take place during the reaction by

1

H-NMR

spectroscopy due to the formation of diastereomers. To our delight,

the triazole product 5a was afforded in an isolated yield of 48%.

However, a diasteriomeric ratio (d.r.) about 70:30 was observed by

1

H-NMR spectroscopy of the crude reaction mixture (Table 1).

11

Reducing the temperature to 60 °C and 50 °C enhanced the d.r. to

about 80:20. Nevertheless, a reduction in the yield of 45% and 40%,

respectively, was obtained (Entry 2 and 3, Table 1).

Based on the

results, it was suspected that AcOH could play an important role in

the observed racemization as well as in the reaction yields due to

the formation of byproducts that were detected by inspection of

the

1

H-NMR of the reaction crude. Hence, three new reaction

conditions were performed without adding AcOH in toluene at 100

°C, 60 °C and 50 °C, 24 h. The desired products were formed in 50%,

60% and 40% yields, respectively, without racemization (Entry 5, 6

and 7, Table 1). Nevertheless some byproducts were detected when

the reaction was performed at 100 °C. This result could explain the

reduction in the yield at this temperature.

It is important to note that the acidic catalyst is not really needed

for these reactions to proceed provided enough time is given (24h).

The racemization might be attributed to the protonation of diverse

species under acidic conditions for instance, the carbonyl of the

ester group, the intermediates enamine and imine or the triazole

final product. All species have a relatively acidic hydrogen at the

chiral center that may be susceptible to racemization. Then, further

experiments were set up to study the influence of the ester group

in the amino acid on the yield and the d.r. using 3 and the methyl

(4b), ethyl (4c) or benzyl ester (4d) of

L

-phenylalanine.

11

In all cases,

the desired products were obtained without racemization and also

a dependence was determined between the size of the ester

substituent and the yield of the reaction with t-Bu> Et> Me> Bn

(see, Entry 1-3, Table S2, ESI).

11

Further screening of temperature and reaction times using 1.0

equivalent of

β

-tetralone (

6

) (readily available), 1.4 equiv of

4a

and 1.2 equiv of PNA

(Table 2) led to the best reaction

condition (entry 4). Moreover, the enantiomeric excess (e.e.),

determined by chiral HPLC, was not affected neither by the

reaction time nor the temperature. In addition, the yields (89-

93%) were independent of the temperature for reaction times

close to 24 hours (Entry 6-8, Table 2), nonetheless the yield

was reduced to 75% at 50 °C. Moreover, for higher reaction

times of around 48 hours a strong dependence of the

temperature was observed and the yields dropped from 90%

to 61% (entry 1-4, Table 2).

Table 1. Synthesis of derivative 5a applying the previously reported conditions.

9a

Entry

T (°C)

additive

Time (h)

d.

r

.

c

Yield (%)

1

b

100 AcOH 24 70/30 48

2

b

60

AcOH

24

80/20

45

3

b

50 AcOH 24 80/20 40

4

100

-------

24

>95

50

5 60 ------- 24 >95 60

6

50

-------

24

>

95

40

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With the optimized reaction conditions in hand, we set out to

explore the substrate scope of the reaction with a range of different

amino esters and cyclic ketones (Table 3). Firstly, the reaction was

performed using 4a and a series of diverse commercially available

ketones. It was demonstrated that this reaction showed good

functionalization group compatibility obtaining the desired

compounds in good yields of 56-71% (Table 3, 5b-5g). Notably, we

did not observe any effect produced by the presence of a

heteroatom in the cyclic ketones, obtaining the triazoles 5f and 5g

in 60% and 65% yields, respectively. In addition, we also did not

observe any tendency related to the bulkiness of the substituent

(5b, 5c, 5d). However, when 5b was compared with 5c a strong

electron donating effect of the methoxy groups was detected. As a

consequence, the yield was reduced from 93% (5b) to 56% (5c). We

hypothesized that, the methoxy groups reduce the rate to form the

enamine intermediate which is an initial and essential intermediate

towards the triazole formation.

9a

Secondly, we proceeded to explore the scope of the amino acid

derivatives using tyrosine,

L

-Phe-

L

-Phe, glutamic acid, and serine

derivatives. The products were obtained in good to moderate yields

(40-61%, 5h-5k). It was found that when serine with the free -OH

group was employed, the desired triazole product was obtained in

only 10% yield, increasing the time and/or the temperature did not

show any improvement, and at 100 °C for 48 h the yield was

actually reduced to 2%. Gratifyingly, when Ot-Bu protected serine

was employed the yield of the reaction reached 50% (5i) at 60 °C for

24 h. It is important to mention that this detrimental effect of a free

hydroxyl group was not observed when tyrosine was employed. As

an example of the broad scope the dipeptide triazole derivative

L

-

Phe-

L

-Phe (5h) was obtained in 61% yield.

Thirdly, since semisynthetic natural products have been highlighted

as a potential source of molecular diversity in drug design

strategies, we decided to embark on the synthesis of triazole

derivatives of natural origin of triazole derivatives of ketones of

natural origin. In this regard, we used as natural source 3 and

dihydrotestosterone and as amino ester substrate 4a and tyrosine

tert-butyl ester. To our delight, the desired products were isolated

in good yields (59-71%, 5a, 5l-5p, Fig. 2). Furthermore, the

racemization did not take place as evidenced by the

1

H-NMR

spectra of the crude reaction mixtures. The reaction was also

shown to be compatible with natural ketones or/and amino esters

containing a free hydroxy group (5m-5p) as well as not to be

affected by using both enantiomers of 4a (5a and 5l, 5n and 5o).

Next, we examined the scope of this protocol towards the synthesis

of 1,5-disubstitutued –1,2,3-triazoles starting from diversely

substituted, commercially available acetophenones. In this regard, a

reaction was performed, using the procedure described above, with

Table 2. Optimal reaction conditions screening.

Entry

T (°C)

Time (h)

e.e

.

b

Yie

ld

c

(%)

1 50 48 >99 84

2

60

48

>99

90

3

70

48

>99

72

4 80 48 >99 61

5

50

24

>99

75

6

60

24

>99

93

7 70 24 >99 91

8

80

24

>99

89

9

RT

24

--

trace

10 RT 48 -- trace

aReactions conditions: Toluene (1.5 M), 1.0 equiv of 6, 1.2

equiv of PNA and 1.4 equiv of 4a. be.e. determined by chiral

HPLC analysis.11 Isolated yield after purification by column

chromatography.

Table 3.

D

iverse libraries of 4,5

-

fused

-

1,2,3

-

triazoles.

Reaction conditions: Toluene (1.5 M), 1.0 equiv of the ketone,

1.2 equiv of PNA and 1.4 equiv of the amino ester at 60 °C 24h.

Fig. 2. Natural products triazole derivatives.

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acetophenones, 4a and PNA. Under these reaction conditions the

product 8a was obtained with a low yield around 10%. Apparently,

the enamines derived from open chain ketones are less reactive

than the highly strained cyclic enamines. Notably, when the

temperature was increased to 80 °C and 100 °C the yield of the

reaction increased to 56% and 71% respectively (Table S3, ESI).

11

In

addition, a prolonged reaction time of 48 hours at 100 ºC did not

affect considerably the yield of the reaction (60%).

On the base of the results obtained, we decided for further work

with these less reactive open chain ketones to modify our initial

reaction protocol, increasing the temperature from 60 °C to 100 °C

at 24 h. It is important to mention that this change did not produce

any effect on the e.e. of the product obtained as determined

previously (ESI).

11

Then, the scope of the reaction was studied

initially, using 4a and diversely functionalized substituted aromatic

ketones (Table 4). The results obtained showed that the reaction is

independent of the electron rich (8b, 8c) or electron deficient

nature (8d-8f, 8h) of the ketone. Besides, we also examined diverse

heterocyclic ketones (8g-8j). To our delight, various interesting

heterocyclic moieties such as indole (8g) and furan (8i) were

amenable to the reaction providing access to triazole derivatives

with 41% and 69% yield respectively which are otherwise difficult to

synthesize. The utility of this reaction was further demonstrated by

the transformation of acetyl ferrocene. With a respect to the

remaining acetylferrocene which was not consumed, the reaction

conversion was about 20% (determined by

1

H-NMR); the desired

product was isolated in 12% yield. Despite of the low yield, it is

important to mention that this is the first time that an 1,5-

disubstituted 1,2,3-triazole derivative of ferrocene, containing an

amino acid is synthesized without using a protecting and

deprotecting strategy.

12

The presented example represents a new

alternative to synthesize novel unexplored ferrocene derivatives

with potential biological applications in a straightforward manner.

12

Our interest in skeletal diversity also led us to investigate the

synthesis of 1,4,5-trisubstituted 1,2,3-triazoles using 5-nonanone

and propiophenone under the same reaction conditions. In this

regard, 8k and 8l were obtained in 20% and 61% yield,

respectively. Then the amino ester diversity scope was examined,

the reaction tolerated glycine ester without lateral chain (8m) in

excellent yield (91%), and alkyl (8n) and aromatic (8o) lateral chains

were also successfully introduced and the desired products were

obtained with 71% and 63% yield respectively.

Finally, the free carboxylic acid derivative was prepared by

hydrolysis of 5a in acidic conditions. Fortunately, the carboxylic acid

derivative 9a (Fig. S39. ESI) was obtained with a 90% yield, besides

no racemization was detected by

1

H-NMR spectra of the crude

reaction mixture (see Fig. S40 ESI). Notably, attempts to prepare

unprotected derivative 9a directly from cholestanone 3 and

phenylalanine failed due to the insolubility of the amino acid in

toluene

Conclusions

In summary, we have developed the synthesis of

enantiomerically pure 1,4,5-trisubstituted, 1,5-disubstituted,

and fused 1,2,3-triazole derivatives of enantiomerically pure

amino acids, using commercially available ketones and amino

esters derived from amino acids under metal-free conditions.

The presented work provides an easy access to diversely

functionalized 1,2,3-triazoles that are inaccessible by other

means. The products were often obtained with very good

yields and in all cases with retention of the chiral centre.

Furthermore, the reaction showed to be widely tolerating

aromatic and heteroaromatic substituted ketones,

heterocycles, fused heterocycles and alkyl ketones. Besides,

natural products such as 5

α

-cholestan-3-one and

dihydrotestosterone were also tolerated giving a new

straightforward manner to modify biologically active

compounds. In addition, the carboxylic acid was also obtained

without racemization, making all the synthesized compounds

valuables amino acid mimetic synthons to be further employed

for medicinal syntheses as well as the construction of more

complex structures for supramolecular chemistry.

Table 4. Diverse libraries of 1,5-disubstituted –1,2,3 triazoles.

Reaction conditions: Toluene (1.5 M), 1.0 equiv of the ketone,

1.2 equiv of PNA and 1.4 equiv of the amino ester at 100 °C

24h.

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Experimental Section

General experimental methods

NMR spectra were acquired on commercial instruments (Bruker

Avance 300 MHz, Bruker AMX 400 MHz or Bruker Avance II+ 600

MHz) and chemical shifts (δ) are reported in parts per million (ppm)

referenced to tetramethylsilane (

1

H), or the internal (NMR) solvent

signal (

13

C). Exact mass spectra were acquire on a quadrupole

orthogonal acceleration time-of-flight mass spectrometer (Synapt

G2 HDMS, Waters, Milford, MA). Samples were infused at 3uL/min

and spectra were obtained in positive (or: negative) ionization

mode with a resolution of 15000 (FWHM) using leucine enkephalin

as lock mass. Melting points (not corrected) were determined using

a Reichert Thermovar apparatus. For column chromatography 70-

230 mesh silica 60 (E. M. Merck) was used as the stationary phase.

Chemicals received from commercial sources were used without

further purification. Dry- reaction solvents (toluene, DMF and

DMSO) were used as received from commercial sources. Reactions

were monitored using thin-layer chromatography (TLC) on

aluminum packed percolated Silica Gel 60 F254 plates. Flash column

chromatography was carried out with silica gel 60 (particle size less

than 0.020 mm) by using appropriate mixtures of ethyl acetate and

hexanes as eluent. Compounds were visualized on the TLC plates by

use of UV light. Anhydrous magnesium sulfate was used for drying

solutions. Chemical nomenclature was generated using Chem Bio

Draw Ultra 13.0.

General procedure for the synthesis of 5a-5p

Ketone (1 eq.), amino ester (1.4 eq.), 4-nitrophenyl azide (1.2 eq), 4

Å molecular sieves (50 mg) and toluene (1.5 M) were mixed in a

sealed reaction tube for 24 hours at 60 °C. After the solvent was

removed under reduced pressure and the crude reaction mixture

was purified by flash column chromatography.

5a. Yellow solid; M.p. 165 – 167 °C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 9:1).

1

H NMR (400 MHz, CDCl

3

): δ 7.19 - 7.15 (m, 3H),

6.98 - 6.96 (m, 2H), 4.98 (t, J = 8.0 Hz, 1H), 3.53 (d, J = 7.8 Hz, 2H),

2.78 (d, J = 15.7 Hz, 1H), 2.26 - 2.20 (m, 2H), 2.04 - 2.01 (m, 1H),

1.85 - 1.77 (m, 1H), 1.69 - 1.65 (m, 1H), 1.57 - 1.50 (m, 4H), 1.43 (s,

9H), 1.34 - 0.97 (m, 17 H), 0.92 (d, J = 6.4 Hz, 4H), 0.88 - 0.85 (m,

7H), 0.65 (s, 3H), 0.44 (s, 3H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ

166.9, 142.8, 136.4, 131.5, 1290, 128.6, 127.0, 83.2, 63.2, 56.2,

53.5, 42.4, 42.0, 39.8, 39.5, 37.4, 36.7, 36.1, 36.0, 35.8, 35.5, 31.5,

29.7, 28.2, 28.0, 27.9, 24.5, 24.3, 23.8, 22.8, 22.6, 21.1, 18.7, 11.9,

11.3 ppm; HRMS (ESI

+

): m/z calcd for C

40

H

61

N

3

O

2

[M+H]

+

616.4797;

found 616.4836.

5l. Yellow solid; M.p. 165 – 167 °C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 9:1).

1

H NMR (400 MHz, CDCl

3

) δ 7.21 - 7.18 (m, 3H),

7.07 - 7.05 (m, 2H), 5.10 (dd, J = 6.2, 9.4 Hz, 1H), 3.58 - 3.54 (m, 2H),

2.80 (d, J = 15.7 Hz, 1H), 2.29 - 2.20 (m, 2H), 2.08 - 2.01 (m, 2H),

1.84 - 1.80 (m, 1H), 1.71 - 1.67 (m, 2H), 1.58 - 1.50 (m, 4H), 1.39 (s,

9H), 1.34 - 0.98 (m, 15H), 0.91 (d, J = 6.5 Hz, 4H), 0.86 (d, J = 5.9 Hz,

7H), 0.65 (d, J = 7.18 Hz, 6H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ 11.4,

11.9, 18.7, 21.1, 22.6, 22.8, 23.8, 24.3, 24.8, 27.8, 28.0, 28.2, 20.0,

31.6, 35.5, 35.8, 36.0, 36.1, 36.7, 39.5, 39.9, 39.9, 42.1, 42.4, 53.5,

56.2, 63.3, 83.1, 127.0, 128.6, 128.9, 131.4, 136.2, 143.2, 167.1

ppm; HRMS (ESI

+

): m/z calcd for C

40

H

61

N

3

O

2

[M+H]

+

616.4797;

found 616.4836.

5b. Red brown solid M.p. 82 - 84 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 8:2).

1

H NMR (400 MHz, CDCl

3

) δ 7.92 (d, J = 7.6 Hz,

1H), 7.31 - 7.27 (m, 1H), 7.20 - 7.17 (m, 5H), 7.06 - 7.04 (m, 2H),

5.22 (dd, J = 6.2, 9.3 Hz, 1H), 3.62 - 3.52 (m, 2H), 2.96 - 2.80 (m, 2H),

2.68 (ddd, J = 7.3, 9.0, 16.1 Hz, 1H), 2.58 - 2.50 (m, 1H), 1.43 (s, 9H)

ppm;

13

C NMR (100 MHz, CDCl

3

) δ 166.8, 143.2, 135.9, 133.4, 133.3,

129.0, 128.7, 128.0, 127.3, 127.2, 127.2, 122.1, 83.5, 63.6, 37.3,

28.5, 27.8, 19.5 ppm; HRMS (ESI

+

): m/z calcd for C

23

H

25

N

3

O

2

[M+H]

+

:

376.2025 found 376.2034

.

5c. Brown solid M.p. 91 – 93 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 8:2).

1

H NMR (400 MHz, CDCl

3

) δ 7.48 (s, 1H), 7.23 -

7.16 (m, 3H), 7.06 - 7.04 (m, 2H), 6.71 (s, 1H), 5.22 (dd, J = 6.2, 9.2

Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.62 - 3.52 (m, 2H), 2.91 - 2.75 (m,

2H), 2.72 - 2.64 (m , 1H), 2.57 - 2.50 (m, 1H), 1.43 (s, 9H) ppm;

13

C

NMR (100 MHz, CDCl

3

) δ 166.8, 148.2, 148.1, 143.4, 135.9, 132.4,

129.0, 128.7, 127.2, 125.6, 121.4, 111.6, 105.6, 83.5, 63.7, 56.1,

56.0, 37.3, 28.2, 27.9, 12.97 ppm; HRMS (ESI

+

): m/z calcd for

C

25

H

29

N

3

O

4

[M+H]

+

: 436,2236; found 436.2226.

5d. Yellow semi-solid. (CH

2

Cl

2

followed by petroleum ether/EtOAc =

8:2).

1

H NMR (400 MHz, CDCl

3

) δ 7.33 - 7.18 (m, 8H), 7.08 - 7.01 (m,

2H), 5.13 – 5.05 (m, 1H), 3.60 - 3.56 (m, 2H), 3.12 - 3.03 (m, 1H),

2.89 - 2.75 (m, 2H), 2.58 - 2.37 (m, 1H), 2.19 - 1.74 (m, 3H), 1.43 +

1.42 (s, 9H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ 167.0, 166.9, 144.9,

144.8, 143.3, 143.1, 136.2, 132.6, 132.4, 129.0, 128.9, 128.6, 128.5,

127.1, 126.9, 126.8, 126.5, 83.3, 63.4, 63.3, 40.5, 40.2, 37.1, 37.0,

30.0, 29.8, 29.6, 29.3, 27.8, 20.1, 19.7 ppm; HRMS (ESI+): m/z calcd

for C

25

H

29

N

3

O

24

[M+H]+: 404.2293; found 404.2336.

5e. Yellow oil. (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3).

1

H

NMR (400 MHz, CDCl

3

) δ 7.22-7.19 (m, 3H), 7.04 - 7.02 (m, 2H), 5.03

(dd, J = 7.3, 8.8 Hz, 1H), 3.57 - 3.56 (m, 2H), 2.74 - 2.65 (m, 2H), 2.41

- 2.36 (m, 1H), 2.14 - 2.09 (m, 1H), 1.76 - 1.62 (m, 4H), 1.41 (s, 9H)

ppm;

13

C NMR (100 MHz, CDCl

3

) δ 20.2, 21.9, 22.4, 22.6, 27.8, 37.1,

63.1, 83.1, 127.0, 128.5, 129.0, 132.8, 136.3, 143.0, 167.0 ppm;

HRMS (ESI

+

): m/z calcd for C

19

H

25

N

3

O

2

[M+H]

+

: 328.1980; found

328.2019.

5f. Brown solid M.p. 80 - 81 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.28-7.18 (m, 3H),

7.04-7.01 (m, 2H), 5.15 (dd, J = 6.3, 9.6 Hz, 1H), 4.77 (ABsyst, J =

13.8 Hz, 2H), 3.89-3.84 (m, 1H), 3.71-3.66 (m, 1H), 349-3.60 (m, 2H),

2.57 (dt, J = 5.7, 5.8 Hz. 1H), 2.33 (dt, J = 4.9, 15.8 Hz, 1H), 1.42 (s,

9H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ 22.0, 27.8, 37.2, 63.6, 63.8,

63.9, 83.5, 127.3, 128.7, 128.9, 130.4, 135.9, 141.3, 166.8 ppm;

HRMS (ESI+): m/z calcd for C

18

H

23

N

3

O

3

[M+H]+: 330.1773; found

330.1808.

5g. Yellow solid. M.p. 98 – 100 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 7:3).

1

H NMR (300 MHz, CDCl

3

) δ 7.32 - 7.20 (m, 8H),

7.05 - 7.03 (m, 2H), 5.10 (dd, J = 6.3, 9.3 Hz, 1H), 3.74 - 3.59 (m, 4H),

3.57 - 3.50 (m, 2H), 2.77 - 2.72 (m, 1H), 2.61 - 2.47 (m, 2H), 2.32 -

2.26 (m, 1H), 1.41 (s, 9H) ppm.

13

C NMR (100 MHz, CDCl

3

) δ 166.9,

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142.0, 138.0, 136.1, 131.4, 129.0, 128.9, 128.4, 127.3, 127.1, 83.4,

63.5, 61.2, 49.6, 49.0, 37.2, 27.8, 20.8 ppm. HRMS (ESI

+

): m/z calcd

for C

25

H

30

N

4

O

2

[M+H]

+

: 419,2402 found 419,2439.

5h. Yellow semisolid solid.

(CH

2

Cl

2

followed by petroleum

ether/EtOAc = 7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.92 (dd, J = 0.7, 7.6

Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.32-7.12 (m, 10H), 6.91 - 6.89 (m,

2H), 4.93 (dd, J = 4.0, 11.3 Hz, 1H), 4.87 (td, J = 5.3, 15.8, 1H), 3.69

(s, 3H), 4.70 (dd, J = 4.0, 13.8 Hz, 1H), 3.26 (m, 2H), 3.03 (dd, J = 8.0,

13.8 Hz, 1H), 2.82 - 2.74 (m, 1H), 2.61 - 2.51 (m, 2H), 2.04 - 1.96 (m,

1H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ 171.1, 167.2, 143.3, 135.9,

135.5, 134.5, 133.6, 129.2, 128.8, 128.76, 128.73, 128.06, 127.7,

127.3, 127.27, 122.1, 65.1, 53.7, 52.5, 39.7, 37.8, 29.7, 28.1, 18.6

ppm; HRMS (ESI

+

): m/z calcd for C

29

H

28

N

4

O

3

[M+H]

+

: 481.2195;

found 481.2226.

5i. Brown semi- solid. (CH

2

Cl

2

followed by petroleum ether/EtOAc =

8:2).

1

H NMR (400 MHz, CDCl

3

) δ 7.96 (d, J = 7.4 Hz, 1H), 7.30 (td, J =

1.7, 7.5 Hz, 1H), 7.24 - 7.18 (m, 2H), 5.44 (dd, J = 3.5, 5.7 Hz, 1H),

4.16 (dd, J = 5.6, 9.5 Hz, 1H), 3.88 (dd, J = 3.5, 9.5 Hz, 1H), 3.09 -

3.00 (m, 4H), 1.48 (s, 9H), 1.13 (s, 9H) ppm;

13

C NMR (100 MHz,

CDCl

3

) δ 165.6, 143.6, 134.6, 133.9, 128.9, 127.9, 127.2, 127.1,

122.0, 83.3, 77.3, 77.0, 76.7, 73.9, 63.4, 62.2, 28.8, 27.9, 27.3, 20.9

ppm; HRMS (ESI

+

): m/z calcd for C

21

H

29

N

3

O

3

[M+H]

+

: 372,2287;

found 372,2275.

5j. Brown solid m.p. 100 – 102 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 8:2).

1

H NMR (400 MHz, CDCl

3

) δ 7.88 (d, J = 7.5 Hz,

1H), 7.27 - 7.23 (m, 1H), 7.17 – 7.15 (m, 2H), 6.88 (d, J = 8.6 Hz, 2H),

6.66 (d, J = 8.6Hz, 2H), 5.21 (dd, J = 6.8, 8.8Hz, 1H), 3.51 - 3.49 (m,

2H), 2.98 - 2.86 (m, 2H), 2.78 - 2.61 (m, 2H), 1.42 (s, 9H) ppm;

13

C

NMR (100 MHz, CDCl

3

) δ 166.9, 155.5, 143.2, 133.6, 133.4, 130.0,

128.2, 128.0, 127.5, 127.3, 126.9, 122.2, 115.7, 83.6, 63.9, 36.2,

28.5, 27.9, 19.5 ppm. HRMS (ESI

+

): m/z calcd for C

23

H

25

N

3

O

3

[M+H]

+

:

392,1974; found 392.1966.

5k. Brown semi-solid. (CH

2

Cl

2

followed by petroleum ether/EtOAc =

7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.96 (d, J = 7.4 Hz, 1H), 7.32 (td, J =

2.4, 6.5 Hz, 1H), 7.25 - 7.19 (m, 2H), 5.41 (dd, J = 5.3, 10.6 Hz, 1H),

4.24 (q, J = 7.2 Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.11 - 3.07 (m, 2H),

3.02 - 2.87 (m, 2H), 2.74 - 2.66 (m, 1H), 2.63 - 2.54 (m, 1H), 2.40 -

2.25 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1, 3H) ppm;

13

C

NMR (100 MHz, CDCl

3

) δ 172.2, 168.1, 143.9, 133.4, 133.3, 128.5,

128.1, 127.5, 127.3, 122.1, 62.4, 60.8, 60.2, 29.9, 28.5, 26.0, 19.6,

14.1, 14.0 ppm; HRMS (ESI

+

): m/z calcd for C

19

H

23

N

3

O

4

[M+H]

+

:

358.1722; found 358.1762.

5m. Brown solid M.p. 150 – 152 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 8:2).

1

H NMR (400 MHz, CDCl

3

) δ 7.87 (br, 1H), 6.79

(d, J = 8.1 Hz, 2H), 6.63 (d, J = 8.1 Hz, 2H), 5.05 (t, J = 7.8 Hz, 1H),

3.46 (d, J = 8.0 Hz, 2H), 2.73 (d, J = 15.6 Hz, 1H), 2.33 (dd, J = 4.4 Hz,

16.6 Hz, 1H), 2.20 (d, J = 15.9 Hz, 1H), 2.01 - 1.98 (m, 1H), 1.84 - 1.66

(m, 4H), 1.55 - 0.85 (m, 39H), 0.64 (s, 3H), 0.48 (s, 3H) ppm;

13

C

NMR (100 MHz, CDCl

3

) δ 167.0, 155.9, 142.9, 131.9, 129.8, 126.9,

115.6, 83.3, 63.5, 56.2, 53.5, 42.4, 42.0, 39.8, 39.5, 36.7, 36.2, 35.8,

35.7, 35.5, 31.5, 28.9, 28.2, 28.0, 27.9, 24.7, 24.2, 23.8, 22.8, 22.6,

21.1, 18.7, 12.0, 11.2 ppm; HRMS (ESI

+

): m/z calcd for C

40

H

61

N

3

O

3

[M+H]

+

: 632,4791, found 632,4797.

5n. Yellow solid M.p. 160 – 162 °C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 8:2).

1

H NMR (400 MHz, CDCl

3

) δ 7.31-7.17 (m, 3H),

6.98 - 6.96 (m, 2H), 4.98 (t, J = 8.0 Hz, 1H), 3.64 (t, J = 8.6 Hz, 1H),

3.53 (d, J = 7.7 Hz, 2H), 2.79 (d, J = 15.8 Hz, 1H), 2.27 - 2.21 (m, 2H),

2.07 - 2.03 (m, 1H), 1.86 - 1.83 (m, 1H), 1.69 - 1.48 (m, 6H), 1.43 (s,

9H), 1.39 – 0.79 (m, 10H), 0.74 (s, 3H), 0.45 (s, 3H) ppm;

13

C NMR

(100 MHz, CDCl

3

) δ 166.9, 142.7, 136.3, 131.5, 128.9, 128.6, 127.0,

83.2, 81.8, 63.2, 53.6, 50.8, 42.8, 42.1, 37.5, 36.8, 36.6, 36.0, 35.5,

31.1, 30.4, 28.8, 27.9, 24.5, 23.4, 20.7, 11.3, 11.0 ppm; HRMS (ESI

+

):

m/z calcd for C

32

H

45

N

3

O

3

[M+H]

+

: 520.3494, found 520.3531.

5o. Yellow solid M.p. 160 – 162 °C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 8:2).

1

H NMR (400 MHz, CDCl

3

) δ 7.23 - 7.18 (m, 3H),

7.07 - 7.05 (m, 2H), 5.11 (dd, J = 6.2, 9.3 Hz, 1H), 3.65 (t, J = 8.51 Hz,

1H), 3.58 – 3.55 (m, 2H), 2.82 (d, J = 15.4 Hz, 1H), 2.30 - 2.22 (m,

2H), 2.09 - 2.02 (m ,2H), 1.87 - 1.84 (m , 1H), 1.68 - 1.52 (m, 4H),

1.43 - 1.35 (m, 11H), 1.28 – 1.10 (m, 4H), 0.96 - 0.85 (m, 4H), 0.75 (s,

3H), 0.66 (s, 3H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ 143.1, 136.2,

131.3, 128.9, 128.6, 127.0, 83.2, 81.8, 63.4, 53.6, 50.8, 42.8, 42.1,

36.8, 36.7, 36.1, 36.0, 35.5, 31.1, 30.4, 28.8, 27.8, 24.8, 23.4, 20.7,

11.4, 11.0 ppm; HRMS (ESI

+

): m/z calcd for C

32

H

45

N

3

O

3

[M+H]

+

:

520.3494, found 520.3531.

5p. Yellow solid M.p. 155 - 156 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 8:2).

1

H NMR (400 MHz, CDCl

3

) δ 8.62 (br, 1H), 6.75

(d, J = 8.0 Hz, 2H), 6.64 (d, J = 8.0 Hz, 2H), 4.98 (t, J = 8.0 Hz, 1H),

3.66 (t, J = 8.5 Hz, 1H), 3.45 (d, J = 7.8 Hz, 2H), 2.72 (d, J = 15.6 Hz,

1H), 2.32 (dd, J = 4.7, 15.7 Hz, 1H), 2.19 (d, J = 15Hz, 1H), 2.08 – 2.00

(m, 1H), 1.83 (d, J = 11.4Hz, 1H), 1.70 - 1.18 (m, 20H), 1.07 (td, J =

4.0, 13.0 Hz, 1H), 0.97-0.77 (m, 3H), 0.73 (s, 3H), 0.47 (s, 3H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ 155.9, 142.6, 131.9, 129.8, 16.8, 115.6,

83.3, 81.8, 63.5, 53.6, 50.8, 42.8, 42.0, 36.8, 36.6, 36.3, 35.8, 35.5,

31.1, 30.3, 28.8, 27.9, 24.6, 23.4, 20.7, 11.3, 11.1 ppm; HRMS (ESI

+

):

m/z calcd for C

32

H

45

N

3

O

4

[M+H]

+

: 536,3488; found 536,3483.

General procedure for the synthesis of 8a-8p

Ketone (1 eq.), amino ester (1.3 eq.), 4-nitrophenyl azide (1.1 eq) 4

Å molecular sieves (50 mg) and toluene 1.5 M were mixed in a

sealed reaction tube for 24 hours at 100 °C. After the solvent was

removed under reduced pressure, the crude reaction mixture was

purified by flash column chromatography.

8a. Yellow solid M.p. 94 - 96 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.56 (s, 1H), 7.45 –

7.35 (m, J = 7.4 Hz, 1H), 7.35 – 7.28 (m, J = 7.4 Hz, 2H), 7.23 – 7.10

(m, J = 7.0 Hz, 3H), 6.88 (d, J = 7.2 Hz, 2H), 6.77 (d, J = 7.2 Hz, 2H),

4.91 (dd, J = 11.4, 4.2 Hz, 1H), 3.79 – 3.67 (m, 1H), 3.55 (dd, J = 14.0,

4.2 Hz, 1H), 1.41 (s, 9H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ 166.8,

139.4, 136.3, 132.3, 129.4, 129.1, 129.0, 128.7, 128.5, 127.0, 126.6,

83.3, 62.4, 37.3, 27.8 ppm; HRMS (ESI

+

): m/z calcd for C

21

H

23

N

3

O

2

[M+H]

+

: 350.1824; found 350.1859.

8b. Orange solid M.p. 82 - 84 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.53 (s, 2H), 7.21 –

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7.14 (m, 3H), 7.12 (d, J = 7.8 Hz, 2H), 6.89 (d, J = 6.1 Hz, 2H), 6.65 (d,

J = 7.8 Hz, 2H), 4.91 (dd, J = 11.3, 4.2 Hz, 1H), 3.78 – 3.68 (m, 1H),

3.55 (dd, J = 14.1, 4.1 Hz, 1H), 2.37 (s, 3H), 1.40 (s, 9H) ppm;

13

C

NMR (100 MHz, CDCl

3

) δ 166.9, 139.6, 139.5, 136.4, 132.3, 129.4,

129.0, 129.0, 128.5, 126.9, 123.5, 83.2, 62.3, 37.3, 27.8, 21.3 ppm;

HRMS (ESI

+

): m/z calcd for C

22

H

25

N

3

O

2

[M+H]

+

: 364.1980; found

364.2016.

8c. Yellow-brown oil. (CH

2

Cl

2

followed by petroleum ether/EtOAc =

7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.51 (s, 1H), 7.23 – 7.11 (m, 3H),

6.89 (d, J = 6.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz,

2H), 4.89 (dd, J = 11.4, 4.1 Hz, 1H), 3.82 (s, 3H), 3.77 – 3.67 (m, 1H),

3.54 (dd, J = 14.0, 4.1 Hz, 1H), 1.41 (s, 9H) ppm;

13

C NMR (100 MHz,

CDCl

3

) δ 166.9, 160.5, 139.3, 136.4, 132.3, 130.5, 129.1, 128.5,

127.0, 118.5, 114.2, 83.2, 62.3, 55.3, 37.3, 27.8 ppm; HRMS (ESI

+

):

m/z calcd for C

22

H

25

N

3

O

3

[M+H]

+

: 380.1929; found 380.1967.

8d. Yellow solid M.p. 62 - 64 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.56 (s, 1H), 7.30

(dd, J = 14.0, 7.6 Hz, 1H), 7.23 – 7.13 (m, 3H), 7.13 – 7.06 (m, 1H),

6.87 (d, J = 6.9 Hz, 2H), 6.58 (d, J = 7.6 Hz, 1H), 6.41 (d, J = 9.1 Hz,

1H), 4.88 (dd, J = 11.5, 4.0 Hz, 1H), 3.77 – 3.67 (m, 1H), 3.55 (dd, J =

14.1, 4.0 Hz, 1H), 1.42 (s, 9H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ

166.6, 163.7, 161.2, 138.3, 138.3, 136.2, 132.4, 130.5, 130.4, 129.0,

128.6, 128.5, 128.5, 127.1, 124.9, 124.9, 83.5, 62.6, 37.3, 27.8 ppm;

HRMS (ESI

+

): m/z calcd for C

21

H

22

FN

3

O

2

[M+H]

+

368.1730; found

368.1764.

8e. Yellow solid M.p. 87 - 89 ˚C (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.54 (s, 1H), 7.23 –

7.12 (m, 3H), 7.00 (t, J = 8.4 Hz, 2H), 6.86 (d, J = 6.9 Hz, 2H), 6.73 –

6.67 (m, 2H), 4.82 (dd, J = 11.5, 4.0 Hz, 1H), 3.77 – 3.67 (m, 1H), 3.53

(dd, J = 14.0, 3.9 Hz, 1H), 1.42 (s, 9H) ppm;

13

C NMR (101 MHz,

CDCl

3

) δ 166.7, 164.6, 162.1, 138.5, 136.4, 132.4, 131.2, 131.1,

129.0, 128.6, 127.0, 122.5, 122.5, 116.0, 115.8, 83.4, 62.5, 37.3,

27.8 ppm; HRMS (ESI

+

): m/z calcd for C

21

H

22

FN

3

O

2

[M+H]

+

368.1730;

found 368.1762.

8f. Yellow-brown oil. (CH

2

Cl

2

followed by petroleum ether/EtOAc =

7:3).

1

H NMR (400 MHz, CDCl

3

) δ 8.17 (d, J = 8.5 Hz, 2H), 7.64 (s,

1H), 7.25 – 7.13 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 7.1 Hz,

2H), 4.81 (dd, J = 11.6, 3.8 Hz, 1H), 3.79 – 3.67 (m, 1H), 3.55 (dd, J =

14.1, 3.7 Hz, 1H), 1.44 (s, 9H) ppm;

13

C NMR (101 MHz, CDCl

3

) δ

166.2, 148.4, 137.5, 136.2, 133.1, 132.8, 130.1, 129.0, 128.8, 127.3,

123.9, 83.8, 63.0, 37.4, 27.8 ppm; HRMS (ESI

+

): m/z calcd for

C

21

H

22

N

4

O

4

[M+H]

+

: 395.1675; found 395.1711.

8g. Off white solid. M.p. 155 - 156 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 7:3).

1

H NMR (400 MHz, CDCl

3

) δ 8.92 (s, 1H), 7.68 (s,

1H), 7.44 (d, J = 8.2 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.21 – 7.05 (m, 5H),

6.88 (d, J = 6.9 Hz, 2H), 6.57 – 6.52 (m, 1H), 5.04 (dd, J = 11.2, 4.2

Hz, 1H), 3.79 – 3.69 (m, 1H), 3.56 (dd, J = 14.0, 4.2 Hz, 1H), 1.41 (s,

9H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ 167.2, 136.6, 135.8, 133.4,

133.2, 129.2, 128.5, 126.9, 126.6, 124.7, 123.0, 120.8, 119.0, 111.5,

101.3, 83.2, 62.4, 37.6, 27.8 ppm; HRMS (ESI

+

): m/z calcd for

C

23

H

24

N

4

O

2

[M+H]

+

389.1933; found 389.1965.

8h. Yellow-brown oil. (CH

2

Cl

2

followed by petroleum ether/EtOAc =

7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.94 – 7.83 (m, 2H), 7.65 (s, 1H),

7.60 – 7.33 (m, 3H), 7.26 – 7.04 (m, 4H), 6.93 – 6.73 (m, 2H), 5.84

(bs, 1H), 4.61 (bs, 1H), 3.90 – 3.60 (m, 1H), 3.49 (dd, J = 13.9, 3.7 Hz,

1H), 1.40 (s, 9H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ 166.9, 137.4,

136.4, 133.7, 133.2, 132.0, 130.2, 129.3, 128.8, 128.7, 128.6, 128.4,

128.2, 127.0, 126.4, 126.1, 125.9, 124.8, 113.4, 83.4, 62.6, 27.8

ppm; HRMS (ESI

+

): m/z calcd for C

25

H

25

N

3

O

2

[M+H]

+

: 400.2010;

found 400.2012.

8i. Brown solid M.p. 63 - 65 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.77 (s, 1H), 7.51

(dd, J = 1.8, 0.8 Hz, 1H), 7.20 – 7.14 (m, 3H), 7.11 – 7.06 (m, 2H),

6.49 (dd, J = 3.4, 1.8 Hz, 1H), 6.47 (dd, J = 3.5, 0.7 Hz, 1H), 5.53 (dd, J

= 9.3, 6.1 Hz, 1H), 3.74 (d, J = 5.7 Hz, 1H), 3.71 (d, J = 2.4 Hz, 1H),

1.37 (s, 9H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ 167.1, 143.7, 141.2,

136.4, 132.0, 129.7, 129.0, 128.5, 127.0, 111.7, 110.5, 83.3, 64.1,

36.9, 27.7 ppm; HRMS (ESI

+

): m/z calcd for C

19

H

21

N

3

O

3

[M+H]

+

340.1616; found 340.1647.

8j. Dark yellow solid M.p. 123 - 125 ˚C. (CH

2

Cl

2

followed by

petroleum ether/EtOAc = 7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.63 (s,

1H), 7.23 – 7.16 (m, 3H), 7.05 – 6.97 (m, 2H), 5.17 (dd, J = 10.8, 4.4

Hz, 1H), 4.30 – 4.22 (m, 3H), 4.03 (s, 5H), 3.88 (d, J = 22.1 Hz, 1H),

3.79 (dd, J = 13.8, 11.1 Hz, 1H), 3.61 (dd, J = 14.1, 4.4 Hz, 1H), 1.41

(s, 9H) ppm;

13

C NMR (101 MHz, CDCl

3

) δ 167.1, 137.3, 136.6, 132.9,

129.2, 128.6, 127.0, 83.3, 70.8, 69.6, 69.4, 69.4, 68.9, 68.5, 62.6,

37.2, 27.8 ppm; HRMS (ESI

+

): m/z calcd for C

25

H

27

FeN

3

O

2

[M+H]

+

:

458.1486; found 458.1516.

8k. Yellow oil. (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3).

1

H

NMR (400 MHz, CDCl

3

) δ 7.17 - 1.16 (m, 3H), 7.00 - 6.97 (m, 2H),

4.78 (dd, J = 4.3, 10.7 Hz, 1H), 3.75 - 3.70 (m, 1H), 3.58 (dd, J = 4.3,

13.9 Hz, 1H), 2.56 - 2.48 (m, 2H), 2.30 - 2.23 (m, 1H), 2.16 - 2.08 (m,

1H), 1.72 - 1.63 (m, 3H), 1.39 (s, 9H), 1.13 - 1.03 (m, 4H), 0.89 (t, J =

7.3 Hz, 3H), 0.78 (t, J = 6.6 Hz, 3H) ppm;

13

C NMR (100 MHz, CDCl

3

) δ

167.1, 144.0, 136.8, 134.2, 129.1, 128.5, 126.9, 83.0, 62.6, 37.3,

30.8, 27.8, 26.9, 22.8, 22.2, 21.7, 13.7, 13.6 ppm; HRMS (ESI

+

): m/z

calcd for C

22

H

33

N

3

O

2

[M+H]

+

: 372.2606; found 372.2642.

8l. Yellow solid M.p. 58 - 60 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 7:3).

1

H NMR (400 MHz, CDCl

3

) δ 7.53 (s, 2H), 7.21 –

7.14 (m, 3H), 7.12 (d, J = 7.8 Hz, 2H), 6.89 (d, J = 6.1 Hz, 2H), 6.65 (d,

J = 7.8 Hz, 2H), 4.91 (dd, J = 11.3, 4.2 Hz, 1H), 3.78 – 3.68 (m, 1H),

3.55 (dd, J = 14.1, 4.1 Hz, 1H), 2.37 (s, 3H), 1.40 (s, 9H) ppm.

13

C

NMR (100 MHz, CDCl

3

) δ 166.9, 139.6, 139.5, 136.4, 132.3, 129.4,

129.1, 129.0, 128.5, 127.0, 123.5, 83.2, 62.3, 37.3, 27.8, 21.3 ppm;

HRMS (ESI

+

): m/z calcd for C

22

H

25

N

3

O

2

[M+H]

+

: 364.1980; found

364.2016.

8m. Off white semi solid. (CH

2

Cl

2

followed by heptane/EtOAc = 6:4).

1

H NMR (300 MHz, CDCl

3

) δ 7.75 (s, 1H), 7.49 - 7.47 (m, 3H), 7.41 -

7.37 (m, 2H), 5.04 (s, 1H), 1.39 (s, 9H) ppm;

13

C NMR (75 MHz,

CDCl

3

) δ 165.6, 138.7, 133.0, 129.8, 129.2, 128.7, 126.9, 83.6, 50.3,

27.9 ppm; HRMS (ESI

+

): m/z calcd for C

14

H

18

N

3

O

2

[M+H]

+

: 260.1393,

found 260.1392.

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ARTICLE Journal Name

8 | J . Na me., 2012 , 00 , 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

8n. Yellow oil. (CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2).

1

H

NMR (400 MHz, CDCl

3

) δ 7.70 (s, 1H), 7.53 – 7.47 (m, 3H), 7.42 –

7.36 (m, 2H), 4.59 (d, J = 9.0 Hz, 1H), 2.77 – 2.68 (m, 1H), 1.44 (s,

9H), 1.28 – 1.17 (m, 1H), 1.09 – 0.96 (m, 4H), 0.77 (t, J = 7.4 Hz, 3H)

ppm;

13

C NMR (100 MHz, CDCl

3

) δ 167.15, 139.20, 132.49, 129.64,

129.31, 129.07, 126.98, 82.92, 66.07, 36.62, 27.85, 25.45, 15.85,

10.81 ppm; HRMS (ESI

+

): m/z calcd for C

18

H

25

N

3

O

2

[M+H]

+

:

316.1980; found 316.2021.

8o. Yellow solid. M.p. 140 - 142 ˚C. (CH

2

Cl

2

followed by petroleum

ether/EtOAc = 8:2).

1

H NMR (400 MHz, CDCl

3

) δ 7.55 (s, 1H), 7.47 –

7.31 (m, 3H), 6.87 (d, J = 7.4 Hz, 2H), 6.80 – 6.73 (m, 2H), 6.71 – 6.63

(m, 2H), 4.98 – 4.90 (m, 1H), 3.74 – 3.63 (m, 1H), 3.51 – 3.43 (m,

1H), 1.41 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 166.9, 155.7, 139.8,

132.1, 130.1, 130.1, 129.7, 129.2, 128.8, 127.2, 126.3, 115.6, 83.4,

62.8, 36.3, 27.8 ppm; HRMS (ESI

+

): m/z calcd for C

21

H

23

N

3

O

3

[M+H]

+

:

366.1773; found 366.1808.

9a. 5a (20 mg, 0.03 mmol) was dissolved in 1,4-dioxane (1.0 mL),

then 0.5 mL of 6M HCl (aq) was added at R.T. and the reaction was

stirred 5h at 85 °C. After, the mixture was cooled to R.T. and water

and ether were added. The mixture was then separated and the

aqueous layer was extracted with ether 3 times. The combined

organic fractions were recollected and dried over MgSO

4

, filtered

and the solvent was removed under reduced pressure affording a

mixture of 9a and tert-butanol (100% conversion).

1

H NMR (400

MHz, CDCl

3

) δ 7.20 – 7.19 (m, 3H), 6.93 (m, 2H), 5.03 (dd, J = 3.4,

11.5 Hz, 1H), 3.65 (dd, J = 3.7, 13.7 Hz, 1H), 3.56 – 3.51 (m, 1H), 2.78

(d, J = 15.6 Hz, 1H), 2.22 – 2.17 (m, 2H), 2.05 – 2.03 (m, 2H), 1.87 –

1.84 (m, 2H), 1.67 – 1.66 (m, 2H), 1.56 – 1.51 (m, 4H), 1.41 – 1.32

(m, 7H), 1.20 – 1.09 (m, 5H), 1.06 – 0.98 (m, 4H), 0.94 – 0.88 (m,

11H), 0.67 (s, 3H), 0.38 (s, 1H).

13

C NMR (100 MHz, CDCl

3

) δ 169.1,

143.0, 135.8, 133.0, 128.9, 128.8, 127.3, 62.8, 56.2, 56.1, 53.4, 42.4,

41.7, 39.8, 39.5, 39.07, 36.7, 36.2, 35.8, 35.6, 35.4, 31.4, 29.7, 28.8,

28.2, 28.0, 24.2, 23.8, 22.8, 22.6, 21.1, 18.7, 14.1, 11.9, 11.3. HRMS

(ESI

+

): m/z calcd for C

36

H

53

N

3

O

2

[M+H]

+

560.4171; found 560.4192.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

S.J. acknowledges Erasmus Mundus Lot 13, Euro-India for the

doctoral fellowship. L.B. thanks to the National Sustainability

Programme of MSMT CR (LO1304) for the internship expenses.

G. S-D also thanks to Dr. Manuel Morales Fund for the

postdoctoral fellowship. Mass spectrometry was made

possible by the support of the Hercules Foundation of the

Flemish Government (grant 20100225–7).

Notes and references

1

(a) G. Silveira-Dorta, V.S. Martín, J.M. Padrón. Amino Acids.

2015,

47

, 1527. (b) G. Silveira-Dorta, O.J. Donadel, V.S.

Martín, J.M. Padrón. J. Org. Chem. 2014,

79

, 6775. (c) G.

Silveira- Dorta, I.J. Sousa, M.X. Fernandes, V.S. Martín, J.M.

Padrón. Eur. J. Med Chem. 2015,

96

, 308, (d) M. Gajewski, B.

Seaver, C.S. Esslinger. Bioorg. Med. Chem. Lett. 2007,

17

,

4163.

2

a) M.G. Finn, V.V. Fokin. Chem. Soc. Rev. 2010,

39

, 1221. (b)

C. Chu, R. Liu. Chem. Soc. Rev. 2011,

40

, 2177.

3

(a) V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless.

Angew. Chem. Int. Ed. 2002,

41

, 2596. (b) L. Zhang, X.G.

Chen, P. Xue, H.H.Y. Sun, I.D. Williams, K.B. Sharpless, V.V.

Fokin, G.C. Jia. J. Am. Chem. Soc. 2005,

127

, 15998.

4

(a) W.S. Horne, J.M. Beierle, A. Montero, M.R. Ghadiri.

Angew Chem Int Ed Engl. 2009,

48

, 4718. (b) N.J. Stanley,

D.S. Pedersen, B. Nielsen, T. Kvist, J.M. Mathiesen, H.

Bräuner-Osborne, D.K. Taylor, A.D. Abell. Bioorg Med Chem

Lett. 2010,

20

, 7512. (c) O.J. Ingham, R.M. Paranal, W.B.

Smith, R.A. Escobar, H. Yueh, T. Snyder, J.A. Jr. Porco, J.E.

Bradner, A.B. Beeler, ACS Med. Chem. Lett. 2016,

7

, 929.

5

(a) L.M. Gaetke, C.K. Chow. Toxicology 2003,

189

, 147; (b)

A.J. Link, M.K.S. Vink, N.J. Agard, J.A. Prescher, C.R. Bertozzi,

D.A. Tirrell. Proc. Natl. Acad. Sci. U.S.A. 2006,

103

, 10180.

6

G. Cheng, X. Zeng, J. Shen, X. Wang, X. Cui. Angew. Chem. Int.

Ed. 2012,

51

, 13265.

7

M. Hill, Dimroth Triazole Synthesis, Name Reactions in

Heterocyclic Chemistry II, Wiley-VCH, Weinheim, 2011.

8

(a) S.S. Ramaastry. Angew. Chem. Int. Ed.

2014

, 53, 14310.

(b) G. Bianchetti, P. Dalla Croce, D. Pocar. Tetrahedron Lett.,

1965,

6

, 2043. (c) R. Huisgen, L. Möbius, G. Szeimies. Chem.

Ber. 1965,

98

, 1138.

9

Triazolization:

(a) J. Thomas, S. Jana, J. John, S. Liekens, W.

Dehaen. Chem. Commun. 2016,

52

, 2885; (b) S. Jana, J.

Thomas, W. Dehaen. J. Org. Chem. 2016,

81

, 12426; (c) S.

Jana, S. Iram, J. Thomas, S. Liekens, W. Dehaen. Bioorg. Med.

Chem. 2017,

25

, 3671; (d) V.A. Bakulev, T. Beryozkina, J.

Thomas, W. Dehaen. Accepted. Eur. J. Org. Chem. DOI:

10.1002/ejoc.201701031.

Non-triazolization:

(e) J. Thomas,

S. Jana, S. Liekens, W. Dehaen. Chem. Commun. 2016,

52

,

9236; (f) J. Thomas, J. John, N. Parekh, W. Dehaen. Angew.

Chem. Int. Ed. 2014,

53

, 10155; (g) Review J. John, J. Thomas,

W. Dehaen Chem. Commun. 2015,

51

, 10797.

10

S. Jana, S. Iram, J. Thomas, M.Q. Hayat, C. Pannecouque, W.

Dehaen. M olecules, 2017,

22

, 303.

11

See Experimental Supporting information (ESI).

12

S. David Köster, J. Dittric, G. Gasser, N. Hüsken, I.C. Henao

Castañeda, J.L. Jios, C. O. Della Védova, N. Metzler-Notle.

Organometallics, 2008, 27, 6326.

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Supporting Information

S1

Straightforward synthesis of enantiomerically pure 1,2,3-triazoles

derived from amino esters

Gaston Silveira-Dorta,

a

Sampad Jana,

a

Lucie Borkova,

b

Joice Thomas

a

and Wim Dehaen

*a

a

Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-

3001 Leuven (Belgium)

b

Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky

University in Olomouc, Hnevotinska 1333/5, 779 00 Olomouc (Czech Republic)

E-mail: wim.dehaen@chem.kuleuven.be

Table of Contents

1) General experimental methods------------------------------------------------------------------

S2

2) Methodological studies of 5a and studies on the influence of the ester --------------

-

S3

3) Chiral HPLC spectrum of

5b

and rac

-

5b

------------------------------------------------------

S4

4) Synthesis Procedures of 5a-p--------------------------------------------------------------------

S5

5) Methodological studies of 8a and studies on the influence of the ester--------------- S14

6) Synthesis Procedures of 8a-o--------------------------------------------------------------------

S15

7)

1

H and

13

C NMR spectra for compound 5a-p------------------------------------------------ S24

8)

1

H and

13

C NMR spectra for compound 8a-o------------------------------------------------ S43

9) Synthesis procedure of 9a------------------------------------------------------------------------ S61

10)

1

H and

13

C NMR spectra of 9a----------------------------------------------------------------- S62

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Supporting Information

S2

1. General experimental methods

NMR spectra were acquired on commercial instruments (Bruker Avance 300 MHz, Bruker

AMX 400 MHz or Bruker Avance II+ 600 MHz) and chemical shifts (δ) are reported in parts

per million (ppm) referenced to tetramethylsilane (

1

H), or the internal (NMR) solvent signal

(

13

C). Exact mass spectra were acquired on a quadrupole orthogonal acceleration time-of-

flight mass spectrometer (Synapt G2 HDMS, Waters, Milford, MA). Samples were infused at

3uL/min and spectra were obtained in positive (or: negative) ionization mode with a

resolution of 15000 (FWHM) using leucine enkephalin as lock mass. Melting points (not

corrected) were determined using a Reichert Thermovar apparatus. For column

chromatography 70-230 mesh silica 60 (E. M. Merck) was used as the stationary phase.

Chemicals received from commercial sources were used without further purification. Dry-

reaction solvents (toluene, DMF and DMSO) were used as received from commercial

sources. Reactions were monitored using thin-layer chromatography (TLC) on aluminum

packed percolated Silica Gel 60 F254 plates. Flash column chromatography was carried out

with silica gel 60 (particle size less than 0.020 mm) by using appropriate mixtures of ethyl

acetate and hexanes as eluent. Compounds were visualized on the TLC plates by use of UV

light. Anhydrous magnesium sulfate was used for drying solutions. Chemical nomenclature

was generated using Chem Bio Draw Ultra 13.0.

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Supporting Information

S3

2. Methodological studies of 5a and studies on the influence of the ester

Table S1. Synthesis of derivative 5a applying the previously reported conditions.

12a

Entry

T (°C) Catalyst Time (h) d.r.

b

Yield (%)

1

a

100 AcOH 24 70/30

48

2

a

60 AcOH 24 80/20

45

3 50 AcOH 24 80/20

40

3 100 ------- 24 >95 50

4 60 ------ 24 >95 60

5 60 ------- 48 >95 34

6 70 ------- 24 >95 50

7 70 ------- 48 >95 18

Reactions were carried out in toluene (1.5 M), 1.0 equiv of 3, 1.2 equiv of PNA and 1.4 equiv

of 4a.

a

30% AcOH.

b

d.r. determined by

1

H-NMR analysis of the crude product 5a.

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Supporting Information

S4

Figure S1.

1

H-NMR Comparison of both diastereoisomers of 5a.

Table S2. Influence of the ester 5a-5ac

H

NH2

R1O2C

O

Toluene

4a-4d 3

PNA

5a-5ac

H

N

3

Ph

CO2R1

Entry Product R

1

d.r.

a

Yield (%)

b

1 5a t-Bu >95 60

2 5aa Me >95 36

3 5ab Et >95 50

4 5ac Bn >95 20

Reactions conditions: toluene (1.5 M), 1.0 equiv of the ketone, 1.2 equiv of PNA and

1.4 equiv of the amino ester at 60 °C 24h.

a

d.r. as determined by

1

H-NMR analysis of

the crude product 5a-5ac,

b

pure product after column chromatography.

3. Chiral HPLC-spectrum of 5b and rac-5b

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Supporting Information

S5

Ph

NH

2

t-BuO

2

C

O

6 4a

PNA

N

CO

2

t-Bu

Ph

5b

a

Figure S2. Representative chiral-HPLC analysis of rac-5b and (S) 5b. The enantiomeric

ratio was determined by HPLC analysis in comparison with racemic material (CHIRAL PAK

IB column, 95.0/5.0 isocratic n-heptane/2-propanol, 0.5 mL/min, major isomer: tR = 23.02

min, UV detection at 254.0 nm, 25 ºC).

a

Reactions conditions: toluene (1.5 M), 1.0 equiv of

the ketone, 1.2 equiv of PNA and 1.4 equiv of the amino ester at 60 °C 24h.

4. Synthesis Procedures of 5a-p

H

N

3

Ph

CO

2

t-Bu

5a (59%)

Tert-Butyl (S)-2-((1R,3aS,3bR,5aS,10aS,10bS,12aR)-10a,12a-dimethyl-1-((R)-6-methyl-

heptan-2-yl)-2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[7,8]

phenanthro [2,3-d][1,2,3]triazol-9(1H)-yl)-3-phenylpropanoate: 5α-Cholestan-3-one (46.5

mg, 0.12 mmol), tert-butyl

L

-phenylalaninate (35.4 mg, 0.16 mmol), 4-nitrophenyl azide (21.3

mg, 0.13 mmol), 4 Å molecular sieves (50 mg) and toluene (0.2 mL) were mixed in a sealed

reaction tube for 24 hours at 60 °C. After the solvent was removed under reduced pressure,

the crude reaction mixture was purified by flash column chromatography (CH

2

Cl

2

followed by

petroleum ether/EtOAc = 9:1) affording 5a (43 mg, 59% yield) as a yellow solid m.p. 165 –

N

CO2t-Bu

Ph

(S)-5b

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Supporting Information

S6

167 °C.

1

H NMR (400 MHz, CDCl

3

) δ 7.19 - 7.15 (m, 3H), 6.98 - 6.96 (m, 2H), 4.98 (t, J = 8.0

Hz, 1H), 3.53 (d, J = 7.8 Hz, 2H), 2.78 (d, J = 15.7 Hz, 1H), 2.26 - 2.20 (m, 2H), 2.04 - 2.01

(m, 1H), 1.85 - 1.77 (m, 1H), 1.69 - 1.65 (m, 1H), 1.57 - 1.50 (m, 4H), 1.43 (s, 9H), 1.34 -

0.97 (m, 17 H), 0.92 (d, J = 6.4 Hz, 4H), 0.88 - 0.85 (m, 7H), 0.65 (s, 3H), 0.44 (s, 3H).

13

C

NMR (100 MHz, CDCl

3

) δ 166.9, 142.8, 136.4, 131.5, 1290, 128.6, 127.0, 83.2, 63.2, 56.2,

53.5, 42.4, 42.0, 39.8, 39.5, 37.4, 36.7, 36.1, 36.0, 35.8, 35.5, 31.5, 29.7, 28.2, 28.0, 27.9,

24.5, 24.3, 23.8, 22.8, 22.6, 21.1, 18.7, 11.9, 11.3. HRMS (ESI

+

): m/z calcd for C

40

H

61

N

3

O

2

[M+H]

+

616.4797; found 616.4836.

5l (64%)

Tert-butyl (R)-2-((1R,3aS,3bR,5aS,10aS,10bS,12aR)-10a,12a-dimethyl-1-((R)-6-methyl-

heptan-2-yl)-2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[7,8]

phenanthro- [2,3-d][1,2,3]triazol-9(1H)-yl)-3-phenylpropanoate: The procedure described

above was applied to 5α-cholestan-3-one (46.5 mg, 0.12 mmol), tert-butyl

D

-phenylalaninate

(35.4 mg, 0.16 mmol), 4-nitrophenyl azide (21.3 mg, 0.13 mmol), 4 Å molecular sieves (50

mg) and toluene (0.2 mL). The product was purified by flash column chromatography

(CH

2

Cl

2

followed by petroleum ether/EtOAc = 9:1) affording 5a (44 mg, 64% yield) as a

yellow solid m.p. 165 – 167 °C.

1

H NMR (400 MHz, CDCl

3

) δ 7.21 - 7.18 (m, 3H), 7.07 - 7.05

(m, 2H), 5.10 (dd, J = 6.2, 9.4 Hz, 1H), 3.58 - 3.54 (m, 2H), 2.80 (d, J = 15.7 Hz, 1H), 2.29 -

2.20 (m, 2H), 2.08 - 2.01 (m, 2H), 1.84 - 1.80 (m, 1H), 1.71 - 1.67 (m, 2H), 1.58 - 1.50 (m,

4H), 1.39 (s, 9H), 1.34 - 0.98 (m, 15H), 0.91 (d, J = 6.5 Hz, 4H), 0.86 (d, J = 5.9 Hz, 7H),

0.65 (d, J = 7.18 Hz, 6H).

13

C NMR (100 MHz, CDCl

3

) δ 11.4, 11.9, 18.7, 21.1, 22.6, 22.8,

23.8, 24.3, 24.8, 27.8, 28.0, 28.2, 20.0, 31.6, 35.5, 35.8, 36.0, 36.1, 36.7, 39.5, 39.9, 39.9,

42.1, 42.4, 53.5, 56.2, 63.3, 83.1, 127.0, 128.6, 128.9, 131.4, 136.2, 143.2, 167.1. HRMS

(ESI

+

): m/z calcd for C

40

H

61

N

3

O

2

[M+H]

+

616.4797; found 616.4836.

5aa ( 36%)

Methyl (S)-2-((1R,3aS,3bR,5aS,10aS,10bS,12aR)-10a,12a-dimethyl-1-((R)-6-methyl-

heptan-2-yl)-2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[7,8]

phenanthro[2,3-d][1,2,3]triazol-9(1H)-yl)-3-phenylpropanoate: The procedure described

above was applied to 5α-cholestan-3-one (108 mg, 0.28 mmol), ),

L

-phenylalanine methyl

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S7

ester (70 mg, 0.39 mmol), 4-nitrophenyl azide (51 mg, 0.31 mmol), 4 Å molecular sieves (50

mg) and toluene (0.3 mL). The product was purified by flash column chromatography

(CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2) affording 5aa (66 mg, 36% yield) as a

yellow solid m.p. 150 – 152 °C.

1

H NMR (400 MHz, CDCl

3

) δ 7.17 - 7.16 (m, 3H), 6.93 - 6.90

(m, 2H), 5.00 (dd, J = 5.8, 9.2 Hz, 1H), 3.77 (s, 3H), 3.59 - 3.27 (m, 2H), 2.77 (d, J = 15.4

Hz, 1H), 2.23 - 2.19 (m, 2H), 2.04 - 2.00 (m, 1H), 1.85 - 1.77 (m, 1H), 1.67 - 1.64 (m, 1H),

1.56 - 0.85 (m, 32H), 0.65 (s, 3H), 0.39 (s, 3H).

13

C NMR (100 MHz, CDCl

3

) δ 168.3, 142.8,

136.0, 131.9, 128.9, 128.7, 127.1, 62.2, 56.2, 56.1, 53.5, 53.0, 42.4, 41.9, 39.8, 39.5, 37.8,

36.7, 36.1, 35.9, 35.8, 35.4, 31.5, 28.8, 28.2, 28.0, 24.2, 24.1, 23.8, 22.8, 22.6, 21.1, 18.7.

HRMS (ESI

+

): m/z calcd for C

37

H

55

N

3

O

2

[M+H]

+

: 574.4328, found 574.4381.

5ab (50 %)

Ethyl (S)-2-((1R,3aS,3bR,5aS,10aS,10bS,12aR)-10a,12a-dimethyl-1-((R)-6-

methylheptan-2-yl)-2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-

tetradecahydrocyclopenta[7,8]phenanthro [2,3-d][1,d2,3]triazol-9(1H)-yl)-3-

phenylpropanoate: The procedure described above was applied to 5α-cholestan-3-one

(100 mg, 0.26 mmol), ),

L

-phenylalanine methyl ester (72mg, 0.36 mmol), 4-nitrophenyl azide

(47 mg, 0.28 mmol), 4 Å molecular sieves (50 mg) and toluene (0.3 mL). The product was

purified by flash column chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2)

affording 5ab (81 mg, 50% yield) as a yellow solid m.p. 155 – 156 °C.

1

H NMR (400 MHz,

CDCl

3

) δ 7.19-7.16 (m, 3H), 6.95 - 6.93 (m, 2H), 5.02 (dd, J = 5.8, 9.3 Hz, 1H), 4.24 (q, J =

7.2 Hz, 2H), 3.62 - 3.52 (m, 2H), 2.77 (d, J = 15.5 Hz, 1H), 2.23 - 2.19 (m, 1H), 2.04 - 2.00

(m, 1H), 1.85 - 1.77 (m, 1H), 1.68 - 1.64 (m, 1H), 1.57 - 0.81 (m, 36H), 0.65 (s, 3H), 0.41 (s,

3H).

13

C NMR (100 MHz, CDCl

3

) δ 167.8, 142.8, 136.1, 131.7, 128.9, 128.7, 127.1, 62.4,

62.3, 56.22, 56.19, 53.5, 42.4, 41.9, 39.8, 39.5, 37.7, 36.7, 36.1, 35.9, 35.8, 35.4, 31.5, 28.9,

28.0, 24.3, 24.2, 23.8, 22.8, 22.6, 21.1, 18.7, 14.0, 11.9, 11.3. HRMS (ESI

+

): m/z calcd for

C

38

H

57

N

3

O

2

[M+H]

+

: 588.4484, found 588.4525.

5ac (20 %)

Benzyl (S)-2-((1R,3aS,3bR,5aS,10aS,10bS,12aR)-10a,12a-dimethyl-1-((R)-6-methyl

heptan-2-yl)-2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[7,8]

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S8

phenanthro[2,3-d][1,2,3]triazol-9(1H)-yl)-3-phenylpropanoate: The procedure described

above was applied to 5α-cholestan-3-one (70 mg, 0.18 mmol), ),

L

-phenylalanine benzyl

ester (66mg, 0.25 mmol), 4-nitrophenyl azide (33 mg, 0.20 mmol), 4 Å molecular sieves (50

mg) and toluene (0.2 mL). The product was purified by flash column chromatography

(CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2) affording 5ac (23 mg, 20% yield) as a

yellow solid 164 – 166 °C.

1

H NMR (400 MHz, CDCl

3

) δ 7.35 - 7.15 (m, 8H), 6.95 - 6.92 (m,

2H), 5.20 (s, 2H), 5.08 (dd, J = 6.2, 9.4 Hz, 1H), 3.60 - 3.58 (m, 2H), 2.76 (d, J = 15.8Hz,

1H), 2.22 - 2.14 (m, 2H), 2.03 - 2.00 (m, 1H), 1.84 - 1.77 (m, 1H), 1.66 - 1.63 (m, 1H), 1.56 -

1.50 (m, 3H), 1.42 - 0.85 (m, 29H), 0.65 (s, 3H), 0.38 (s, 3H).

13

C NMR (100 MHz, CDCl

3

) δ

167.7, 142.9, 135.9, 134.9, 131.8, 128.9, 128.7, 128.6, 128.5, 128.4, 127.1, 67.8, 62.44,

56.2, 56.1, 53.5, 42.4, 41.9, 39.8, 39.5, 37.6, 36.7, 36.1, 35.9, 35.8, 35.4, 31.5, 28.8, 28.2,

28.0, 24.3, 24.2, 23.8, 22.8, 22.6, 21.1, 18.7, 11.9, 11.3. HRMS (ESI

+

): m/z calcd for

C

43

H

59

N

3

O

2

[M+H]

+

: 650.4641, found 650.4680.

5b (93%)

Tert-butyl (S)-2-(4,5-dihydro-1H-naphtho[1,2-d][1,2,3]triazol-1-yl)-3-phenylpropanoate.

The procedure described above was applied to β-tetralone (33.6 mg, 0.23 mmol), tert-butyl

L

-

phenylalaninate (70 mg, 0.32 mmol), 4-nitrophenyl azide (42.7 mg, 0.26 mmol), 4 Å

molecular sieves (50 mg) and toluene (0.2 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2) affording 5b (80.2 mg,

93% yield) as a red brown solid m.p. 82 - 84 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.92 (d, J = 7.6

Hz, 1H), 7.31 - 7.27 (m, 1H), 7.20 - 7.17 (m, 5H), 7.06 - 7.04 (m, 2H), 5.22 (dd, J = 6.2, 9.3

Hz, 1H), 3.62 - 3.52 (m, 2H), 2.96 - 2.80 (m, 2H), 2.68 (ddd, J = 7.3, 9.0, 16.1 Hz, 1H), 2.58 -

2.50 (m, 1H), 1.43 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 166.8, 143.2, 135.9, 133.4, 133.3,

129.0, 128.7, 128.0, 127.3, 127.2, 127.2, 122.1, 83.5, 63.6, 37.3, 28.5, 27.8, 19.5. HRMS

(ESI

+

): m/z calcd for C

23

H

25

N

3

O

2

[M+H]

+

: 376.2025 found 376.2034.

5c (56%)

Tert-butyl (S)-2-(7,8-dimethoxy-4,5-dihydro-1H-naphtho[1,2-d][1,2,3]triazol-1-yl)-3-

phenylpropanoate: The procedure described above was applied to 6,7-dimethoxy-2-

tetralone (30 mg, 0.15 mmol), tert-butyl

L

-phenylalaninate (45.1 mg, 0.2 mmol), 4-nitrophenyl

azide (26 mg, 0.16 mmol), 4 Å molecular sieves (50 mg) and toluene (0.2 mL). The product

was purified by flash column chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc =

8:2) affording 5c (35 mg, 56% yield) as a brown solid m.p. 91 – 93 .

1

H NMR (400 MHz,

CDCl

3

) δ 7.48 (s, 1H), 7.23 - 7.16 (m, 3H), 7.06 - 7.04 (m, 2H), 6.71 (s, 1H), 5.22 (dd, J =

6.2, 9.2 Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.62 - 3.52 (m, 2H), 2.91 - 2.75 (m, 2H), 2.72 -

2.64 (m , 1H), 2.57 - 2.50 (m, 1H), 1.43 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 166.8, 148.2,

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S9

148.1, 143.4, 135.9, 132.4, 129.0, 128.7, 127.2, 125.6, 121.4, 111.6, 105.6, 83.5, 63.7, 56.1,

56.0, 37.3, 28.2, 27.9, 12.97. HRMS (ESI

+

): m/z calcd for C

25

H

29

N

3

O

4

[M+H]

+

: 436,2236;

found 436.2226.

5d (71%)

Tert-butyl (2S)-3-phenyl-2-(5-phenyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-1-

yl)propanoate: The procedure described above was applied to 4-Phenylcyclohexanone (50

mg, 0.3 mmol), ), tert-butyl

L

-phenylalaninate (88.5 mg, 0.4 mmol), 4-nitrophenyl azide (54.1

mg, 0.33 mmol), 4 Å molecular sieves (50 mg) and toluene (0.3 mL). The product was

purified by flash column chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2)

affording 5d (85 mg, 71% yield) as a yellow semi-solid.

1

H NMR (400 MHz, CDCl

3

) δ 7.33 -

7.18 (m, 8H), 7.08 - 7.01 (m, 2H), 5.13 – 5.05 (m, 1H), 3.60 - 3.56 (m, 2H), 3.12 - 3.03 (m,

1H), 2.89 - 2.75 (m, 2H), 2.58 - 2.37 (m, 1H), 2.19 - 1.74 (m, 3H), 1.43 + 1.42 (s, 9H).

13

C

NMR (100 MHz, CDCl

3

) δ 167.0, 166.9, 144.9, 144.8, 143.3, 143.1, 136.2, 132.6, 132.4,

129.0, 128.9, 128.6, 128.5, 127.1, 126.9, 126.8, 126.5, 83.3, 63.4, 63.3, 40.5, 40.2, 37.1,

37.0, 30.0, 29.8, 29.6, 29.3, 27.8, 20.1, 19.7. HRMS (ESI+): m/z calcd for C

25

H

29

N

3

O

24

[M+H]+: 404.2293; found 404.2336.

5e (65%)

Tert-butyl (S)-3-phenyl-2-(4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-1-yl)propanoate:

The procedure described above was applied to cyclohexanone (50 mg, 0.51 mmol), ), tert-

butyl

L

-phenylalaninate (157 mg, 0.7 mmol), 4-nitrophenyl azide (90.2 mg, 0.56 mmol), 4 Å

molecular sieves (50 mg) and toluene (0.5 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 5e (97 mg,

65% yield) as a yellow oil.

1

H NMR (400 MHz, CDCl

3

) δ 7.22-7.19 (m, 3H), 7.04 - 7.02 (m,

2H), 5.03 (dd, J = 7.3, 8.8 Hz, 1H), 3.57 - 3.56 (m, 2H), 2.74 - 2.65 (m, 2H), 2.41 - 2.36 (m,

1H), 2.14 - 2.09 (m, 1H), 1.76 - 1.62 (m, 4H), 1.41 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ

20.2, 21.9, 22.4, 22.6, 27.8, 37.1, 63.1, 83.1, 127.0, 128.5, 129.0, 132.8, 136.3, 143.0,

167.0. HRMS (ESI

+

): m/z calcd for C

19

H

25

N

3

O

2

[M+H]

+

: 328.1980; found 328.2019.

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5f (60%)

Tert-butyl (S)-2-(6,7-dihydropyrano[2,3-d][1,2,3]triazol-1(5H)-yl)-3-phenylpropanoate:

The procedure described above was applied to tetrahydro-4H-pyran-4-one (50 mg, 0.5

mmol), tert-butyl

L

-phenylalaninate (155 mg, 0.7 mmol), 4-nitrophenyl azide (90 mg, 0.55

mmol), 4 Å molecular sieves (50 mg) and toluene (0.5 mL). The product was purified by flash

column chromatography (CH

2

Cl

2

) followed by petroleum ether/EtOAc = 7:3) affording 5f (99

mg, 60% yield) as a brown solid m.p. 80 - 81 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.28-7.18 (m,

3H), 7.04-7.01 (m, 2H), 5.15 (dd, J = 6.3, 9.6 Hz, 1H), 4.77 (ABsyst, J = 13.8 Hz, 2H), 3.89-

3.84 (m, 1H), 3.71-3.66 (m, 1H), 349-3.60 (m, 2H), 2.57 (dt, J = 5.7, 15.8 Hz. 1H), 2.33 (dt, J

= 4.9, 15.8 Hz, 1H), 1.42 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 22.0, 27.8, 37.2, 63.6, 63.8,

63.9, 83.5, 127.3, 128.7, 128.9, 130.4, 135.9, 141.3, 166.8. HRMS (ESI+): m/z calcd for

C

18

H

23

N

3

O

3

[M+H]+: 330.1773; found 330.1808.

5g (65%)

Tert-butyl (S)-2-(6,7-dihydropyrano[2,3-d][1,2,3]triazol-1(5H)-yl)-3-phenylpropanoate:

The procedure described above was applied to 1-benzyl-4-piperidone (50 mg, 0.26 mmol),

tert-butyl

L

-phenylalaninate (82 mg, 0.37 mmol), 4-nitrophenyl azide (44 mg, 0.28 mmol), 4 Å

molecular sieves (50 mg) and toluene (0.3 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 5g (70.6 mg,

65% yield) as a yellow solid 98 – 100 ˚C.

1

H NMR (300 MHz, CDCl

3

) δ 7.32 - 7.20 (m, 8H),

7.05 - 7.03 (m, 2H), 5.10 (dd, J = 6.3, 9.3 Hz, 1H), 3.74 - 3.59 (m, 4H), 3.57 - 3.50 (m, 2H),

2.77 - 2.72 (m, 1H), 2.61 - 2.47 (m, 2H), 2.32 - 2.26 (m, 1H), 1.41 (s, 9H).

13

C NMR (100

MHz, CDCl

3

) δ 166.9, 142.0, 138.0, 136.1, 131.4, 129.0, 128.9, 128.4, 127.3, 127.1, 83.4,

63.5, 61.2, 49.6, 49.0, 37.2, 27.8, 20.8. HRMS (ESI

+

): m/z calcd for C

25

H

30

N

4

O

2

[M+H]

+

:

419,2402 found 419,2439

5h (60%)

Methyl ((S)-2-(4,5-dihydro-1H-naphtho[1,2-d][1,2,3]triazol-1-yl)-3-phenylpropanoyl)-L-

phenylalaninate: The procedure described above was applied to β-tetralone (20 mg, 0.14

mmol), methyl

L

-phenylalanyl-

L

-phenylalaninate (62.5 mg, 0.19 mmol), 4-nitrophenyl azide

(24.7 mg, 0.15 mmol), 4 Å molecular sieves (50 mg) and toluene (0.15 mL). The product was

purified by flash column chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3)

affording 5h (39.2 mg, 60% yield) as a yellow semisolid solid.

1

H NMR (400 MHz, CDCl

3

) δ

7.92 (dd, J = 0.7, 7.6 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.32-7.12 (m, 10H), 6.91 - 6.89 (m,

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S11

2H), 4.93 (dd, J = 4.0, 11.3 Hz, 1H), 4.87 (td, J = 5.3, 15.8, 1H), 3.69 (s, 3H), 4.70 (dd, J =

4.0, 13.8 Hz, 1H), 3.26 (m, 2H), 3.03 (dd, J = 8.0, 13.8 Hz, 1H), 2.82 - 2.74 (m, 1H), 2.61 -

2.51 (m, 2H), 2.04 - 1.96 (m, 1H).

13

C NMR (100 MHz, CDCl

3

) δ 171.1, 167.2, 143.3, 135.9,

135.5, 134.5, 133.6, 129.2, 128.8, 128.76, 128.73, 128.06, 127.7, 127.3, 127.27, 122.1,

65.1, 53.7, 52.5, 39.7, 37.8, 29.7, 28.1, 18.6. HRMS (ESI

+

): m/z calcd for C

29

H

28

N

4

O

3

[M+H]

+

: 481.2195; found 481.2226.

5i (50%)

Tert-butyl (S)-3-(tert-butoxy)-2-(4,5-dihydro-1H-naphtho[1,2-d][1,2,3]triazol-1-

yl)propanoate. The procedure described above was applied to β-tetralone (30 mg, 0.20

mmol), O-tert-butyl-

L

-serine tert-butyl ester (65.2 mg, 0.3 mmol), 4-nitrophenyl azide (36 mg,

0.22 mmol), 4 Å molecular sieves (50 mg) and toluene (0.2 mL). The product was purified by

flash column chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2) affording 5i

(37 mg, 50% yield) as a brown semi- solid.

1

H NMR (400 MHz, CDCl

3

) δ 7.96 (d, J = 7.4 Hz,

1H), 7.30 (td, J = 1.7, 7.5 Hz, 1H), 7.24 - 7.18 (m, 2H), 5.44 (dd, J = 3.5, 5.7 Hz, 1H), 4.16

(dd, J = 5.6, 9.5 Hz, 1H), 3.88 (dd, J = 3.5, 9.5 Hz, 1H), 3.09 - 3.00 (m, 4H), 1.48 (s, 9H),

1.13 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 165.6, 143.6, 134.6, 133.9, 128.9, 127.9, 127.2,

127.1, 122.0, 83.3, 77.3, 77.0, 76.7, 73.9, 63.4, 62.2, 28.8, 27.9, 27.3, 20.9. HRMS (ESI

+

):

m/z calcd for C

21

H

29

N

3

O

3

[M+H]

+

: 372,2287; found 372,2275.

5j (58%)

Tert-butyl (S)-2-(4,5-dihydro-1H-naphtho[1,2-d][1,2,3]triazol-1-yl)-3-(4-hydroxyphenyl)

propanoate. The procedure described above was applied to β-tetralone (30.7 mg, 0.21

mmol),

L

-tyrosine tert-butyl ester (71.1 mg, 0.3 mmol), 4-nitrophenyl azide (37 mg, 0.23

mmol), 4 Å molecular sieves (50 mg) and toluene (0.2 mL). The product was purified by flash

column chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2) affording 5j (59

mg, 68% yield) as a brown solid m.p. 100 – 102 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.88 (d, J =

7.5 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.17 – 7.15 (m, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.66 (d, J =

8.6Hz, 2H), 5.21 (dd, J = 6.8, 8.8Hz, 1H), 3.51 - 3.49 (m, 2H), 2.98 - 2.86 (m, 2H), 2.78 -

2.61 (m, 2H), 1.42 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 166.9, 155.5, 143.2, 133.6, 133.4,

130.0, 128.2, 128.0, 127.5, 127.3, 126.9, 122.2, 115.7, 83.6, 63.9, 36.2, 28.5, 27.9, 19.5.

HRMS (ESI

+

): m/z calcd for C

23

H

25

N

3

O

3

[M+H]

+

: 392,1974; found 392.1966.

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S12

5k (40%)

Diethyl (S)-2-(4,5-dihydro-1H-naphtho[1,2-d][1,2,3]triazol-1-yl)pentanedioate: The

procedure described above was applied to β-tetralone (30 mg, 0.21 mmol),

L

-glutamic acid

diethyl ester (58.4 mg, 0.29 mmol), 4-nitrophenyl azide (37 mg, 0.23 mmol), 4 Å molecular

sieves (50 mg) and toluene (0.2 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 5k (29.3 mg,

40% yield) as a brown semi-solid.

1

H NMR (400 MHz, CDCl

3

) δ 7.96 (d, J = 7.4 Hz, 1H),

7.32 (td, J = 2.4, 6.5 Hz, 1H), 7.25 - 7.19 (m, 2H), 5.41 (dd, J = 5.3, 10.6 Hz, 1H), 4.24 (q, J

= 7.2 Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.11 - 3.07 (m, 2H), 3.02 - 2.87 (m, 2H), 2.74 - 2.66

(m, 1H), 2.63 - 2.54 (m, 1H), 2.40 - 2.25 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1,

3H).

13

C NMR (100 MHz, CDCl

3

) δ 172.2, 168.1, 143.9, 133.4, 133.3, 128.5, 128.1, 127.5,

127.3, 122.1, 62.4, 60.8, 60.2, 29.9, 28.5, 26.0, 19.6, 14.1, 14.0. HRMS (ESI

+

): m/z calcd for

C

19

H

23

N

3

O

4

[M+H]

+

: 358.1722; found 358.1762.

5m (60%)

Tert-butyl (S)-2-((1R,3aS,3bR,5aS,10aS,10bS,12aR)-10a,12a-dimethyl-1-((R)-6-methyl

heptan-2-yl)-2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[7,8]

phenanthro[2,3-d][1,2,3]triazol-9(1H)-yl)-3-(4-hydroxyphenyl)propanoate: The

procedure described above was applied to 5α-cholestan-3-one (45 mg, 0.12 mmol), ),

L

-

tyrosine tert-butyl ester (21 mg, 0.13 mmol), 4-nitrophenyl azide (28 mg, 0.16 mmol), 4 Å

molecular sieves (50 mg) and toluene (0.1 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2) affording 5m (34 mg,

60% yield) as a brown solid m.p. 150 – 152 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.87 (br, 1H),

6.79 (d, J = 8.1 Hz, 2H), 6.63 (d, J = 8.1 Hz, 2H), 5.05 (t, J = 7.8 Hz, 1H), 3.46 (d, J = 8.0 Hz,

2H), 2.73 (d, J = 15.6 Hz, 1H), 2.33 (dd, J = 4.4 Hz, 16.6 Hz, 1H), 2.20 (d, J = 15.9 Hz, 1H),

2.01 - 1.98 (m, 1H), 1.84 - 1.66 (m, 4H), 1.55 - 0.85 (m, 39H), 0.64 (s, 3H), 0.48 (s, 3H).

13

C

NMR (100 MHz, CDCl

3

) δ 167.0, 155.9, 142.9, 131.9, 129.8, 126.9, 115.6, 83.3, 63.5, 56.2,

53.5, 42.4, 42.0, 39.8, 39.5, 36.7, 36.2, 35.8, 35.7, 35.5, 31.5, 28.9, 28.2, 28.0, 27.9, 24.7,

24.2, 23.8, 22.8, 22.6, 21.1, 18.7, 12.0, 11.2. HRMS (ESI

+

): m/z calcd for C

40

H

61

N

3

O

3

[M+H]

+

: 632,4791, found 632,4797.

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Supporting Information

S13

5n (65%)

Tert-butyl (S)-2-((1S,3aS,3bR,5aS,10aS,10bS,12aS)-1-hydroxy-3a,10a,12a-trimethyl-

2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[7,8]phenanthro[2,3-

d][1,2,3]triazol-9(1H)-yl)-3-phenylpropanoate.

The procedure described above was

applied to stanolone (50 mg, 0.17 mmol), ), tert-butyl

L

-phenylalaninate (52.6 mg, 0.24

mmol), 4-nitrophenyl azide (31 mg, 0.16 mmol), 4 Å molecular sieves (50 mg) and toluene

(0.2 mL). The product was purified by flash column chromatography (CH

2

Cl

2

followed by

petroleum ether/EtOAc = 8:2) affording 5n (54.4 mg, 65% yield) as a yellow solid m.p. 160 –

162 °C.

1

H NMR (400 MHz, CDCl

3

) δ 7.31-7.17 (m, 3H), 6.98 - 6.96 (m, 2H), 4.98 (t, J = 8.0

Hz, 1H), 3.64 (t, J = 8.6 Hz, 1H), 3.53 (d, J = 7.7 Hz, 2H), 2.79 (d, J = 15.8 Hz, 1H), 2.27 -

2.21 (m, 2H), 2.07 - 2.03 (m, 1H), 1.86 - 1.83 (m, 1H), 1.69 - 1.48 (m, 6H), 1.43 (s, 9H), 1.39

– 0.79 (m, 10H), 0.74 (s, 3H), 0.45 (s, 3H).

13

C NMR (100 MHz, CDCl

3

) δ 166.9, 142.7,

136.3, 131.5, 128.9, 128.6, 127.0, 83.2, 81.8, 63.2, 53.6, 50.8, 42.8, 42.1, 37.5, 36.8, 36.6,

36.0, 35.5, 31.1, 30.4, 28.8, 27.9, 24.5, 23.4, 20.7, 11.3, 11.0. HRMS (ESI

+

): m/z calcd for

C

32

H

45

N

3

O

3

[M+H]

+

: 520.3494, found 520.3531.

5o (65%)

Tert-butyl (R)-2-((1S,3aS,3bR,5aS,10aS,10bS,12aS)-1-hydroxy-3a,10a,12a-trimethyl-

2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[7,8]phenanthro[2,3-

d][1,2,3]triazol-9(1H)-yl)-3-phenylpropanoate: The procedure described above was

applied to stanolone (50 mg, 0.17 mmol), ), tert-butyl

D

-phenylalaninate (52.6 mg, 0.24

mmol), 4-nitrophenyl azide (31 mg, 0.16 mmol), 4 Å molecular sieves (50 mg) and toluene

(0.2 mL). The product was purified by flash column chromatography (CH

2

Cl

2

followed by

petroleum ether/EtOAc = 8:2) affording 5o (54.4 mg, 65% yield) as a yellow solid m.p. 160 –

162 °C.

1

H NMR (400 MHz, CDCl

3

) δ 7.23 - 7.18 (m, 3H), 7.07 - 7.05 (m, 2H), 5.11 (dd, J =

6.2, 9.3 Hz, 1H), 3.65 (t, J = 8.51 Hz, 1H), 3.58 – 3.55 (m, 2H), 2.82 (d, J = 15.4 Hz, 1H),

2.30 - 2.22 (m, 2H), 2.09 - 2.02 (m ,2H), 1.87 - 1.84 (m , 1H), 1.68 - 1.52 (m, 4H), 1.43 - 1.35

(m, 11H), 1.28 – 1.10 (m, 4H), 0.96 - 0.85 (m, 4H), 0.75 (s, 3H), 0.66 (s, 3H).

13

C NMR (100

MHz, CDCl

3

) 143.1, 136.2, 131.3, 128.9, 128.6, 127.0, 83.2, 81.8, 63.4, 53.6, 50.8, 42.8,

42.1, 36.8, 36.7, 36.1, 36.0, 35.5, 31.1, 30.4, 28.8, 27.8, 24.8, 23.4, 20.7, 11.4, 11.0. HRMS

(ESI

+

): m/z calcd for C

32

H

45

N

3

O

3

[M+H]

+

: 520.3494, found 520.3531.

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Supporting Information

S14

5p (71%)

Tert-butyl (S)-2-((1S,3aS,3bR,5aS,10aS,10bS,12aS)-1-hydroxy-10a,12a-dimethyl-

2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[7,8]phenanthro[2,3-

d][1,2,3]triazol-9(1H)-yl)-3-(4-hydroxyphenyl)propanoate: The procedure described

above was applied to stanolone (45 mg, 0.15 mmol), ),

L

-tyrosine tert-butyl ester (50 mg,

0.21 mmol), 4-nitrophenyl azide (28 mg, 0.17 mmol), 4 Å molecular sieves (50 mg) and

toluene (0.2 mL). The product was purified by flash column chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2) affording 5p (67 mg, 71% yield) as a yellow solid

m.p. 155 - 156 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 8.62 (br, 1H), 6.75 (d, J = 8.0 Hz, 2H), 6.64

(d, J = 8.0 Hz, 2H), 4.98 (t, J = 8.0 Hz, 1H), 3.66 (t, J = 8.5 Hz, 1H), 3.45 (d, J = 7.8 Hz, 2H),

2.72 (d, J = 15.6 Hz, 1H), 2.32 (dd, J = 4.7, 15.7 Hz, 1H), 2.19 (d, J = 15Hz, 1H), 2.08 – 2.00

(m, 1H), 1.83 (d, J = 11.4Hz, 1H), 1.70 - 1.18 (m, 20H), 1.07 (td, J = 4.0, 13.0 Hz, 1H), 0.97-

0.77 (m, 3H), 0.73 (s, 3H), 0.47 (s, 3H).

13

C NMR (100 MHz, CDCl

3

) δ 155.9, 142.6, 131.9,

129.8, 16.8, 115.6, 83.3, 81.8, 63.5, 53.6, 50.8, 42.8, 42.0, 36.8, 36.6, 36.3, 35.8, 35.5, 31.1,

30.3, 28.8, 27.9, 24.6, 23.4, 20.7, 11.3, 11.1. HRMS (ESI

+

): m/z calcd for C

32

H

45

N

3

O

4

[M+H]

+

: 536,3488; found 536,3483

5. Methodological studies of 8a and ester influence

Table S3. Influence of the temperature and time on the yield of the reaction

Entry T (°C) Time (h) Yield (%)

1 60 24 10

2 80 24 56

3 100 24 69

4 100 48 60

Reactions were carried out in toluene (1.5 M), 1.0 equiv of 7, 1.2 equiv of PNA and 1.4 equiv

of 4a.

Table S4. Influence of the ester on the yield of the reaction

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Supporting Information

S15

Entry Product R

1

Yiled (%)

1 8a t-Bu 71

2 8aa Me 20

3 8ab Et 41

4 8ac Bn 32

Reaction conditions: toluene (1.5 M), 1.0 equiv of the ketone, 1.2 equiv of PNA and

1.4 equiv of the amino ester at 100 °C 24h.

6. Synthesis procedure of 8a-8o

8a (71%)

Tert-butyl (S)-3-phenyl-2-(5-phenyl-1H-1,2,3-triazol-1-yl)propanoate: The procedure

described above was applied to acetophenone (50 mg, 0.42 mmol), tert-butyl

L

-

phenylalaninate (132 mg, 0.58), 4-nitrophenyl azide (75 mg, 0.46 mmol) 4 Å molecular

sieves (50 mg) and toluene (0.4 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8a (95 mg, 71%

yield) as a yellow solid m.p. 94 - 96 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.56 (s, 1H), 7.45 –

7.35 (m, J = 7.4 Hz, 1H), 7.35 – 7.28 (m, J = 7.4 Hz, 2H), 7.23 – 7.10 (m, J = 7.0 Hz, 3H),

6.88 (d, J = 7.2 Hz, 2H), 6.77 (d, J = 7.2 Hz, 2H), 4.91 (dd, J = 11.4, 4.2 Hz, 1H), 3.79 – 3.67

(m, 1H), 3.55 (dd, J = 14.0, 4.2 Hz, 1H), 1.41 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 166.8,

139.4, 136.3, 132.3, 129.4, 129.1, 129.0, 128.7, 128.5, 127.0, 126.6, 83.3, 62.4, 37.3, 27.8.

(M

+

); HRMS (ESI

+

): m/z calcd for C

21

H

23

N

3

O

2

[M+H]

+

: 350.1824; found 350.1859.

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Supporting Information

S16

8aa (20%)

Methyl (S)-3-phenyl-2- (5-phenyl-1H-1,2,3-triazol-1-yl)propanoate: The procedure

described above was applied to acetophenone (34 mg, 0.28 mmol), methyl

L

-

phenylalaninate (71 mg, 0.40 mmol), 4-nitrophenyl azide (50 mg, 0.31 mmol), 4 Å molecular

sieves (50 mg) and toluene (0.3 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether /EtOAc = 8:2) affording 8aa (15.1 mg,

20% yield) as a yellow solid m.p. 89 - 91 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.56 (s, 1H), 7.41 -

7.37 (m, 1H), 7.33 - 7.29 (m, 2H), 7.19 - 7.12 (m, 3H), 6.85 - 6.82 (m, 2H), 6.75 - 6.73 (m,

2H), 5.03 (dd, J = 4.1, 11.6 Hz, 1H), 3.78 (s, 3H), 3.74 - 3.70 (m, 1H), 3.63 - 3.58 (m, 1H).

13

C NMR (100 MHz, CDCl

3

) δ 168.4, 139.6, 135.9, 132.4, 129.6, 129.1, 129.0, 128.8, 128.6,

127.1, 126.3, 61.6, 53.2, 37.7; HRMS (ESI

+

): m/z calcd for C

18

H

18

N

3

O

2

[M+H]

+

: 308.1393,

found 308.1395.

8ab (44%)

Ethyl (S)-3-phenyl-2-(5-phenyl-1H-1,2,3-triazol-1-yl)propanoate: The procedure

described above was applied to acetophenone (32 mg, 0.26 mmol), ethyl

L

-phenylalaninate

(70 mg, 0.36 mmol), 4-nitrophenyl azide (46 mg, 0.28 mmol), 4 Å molecular sieves (50 mg)

and toluene (0.3 mL). The product was purified by flash column chromatography (CH

2

Cl

2

followed by petroleum ether /EtOAc = 8:2) affording 8ab (37 mg, 44% yield) as a yellow solid

m.p. 92 - 93 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.56 (s, 1H), 7.41 - 7.37 (m, 1H), 7.33 - 7.29

(m, 2H), 7.19 - 7.13 (m, 3H), 6.87 - 6.84 (m, 2H), 6.77 - 6.75 (m, 2H), 5.01 (dd, J = 4.2, 11.4

Hz, 1H), 4.27 - 4.19 (m, 2H), 3.74 (dd, J = 11.4, 13.0 Hz, 1H), 3.60 (dd, J = 4.2, 14.0 Hz,

1H), 1.23 (t, J = 7.1, 3H).

13

C NMR (100 MHz, CDCl

3

) δ 167.9, 139.6, 136.0, 132.4, 129.5,

129.1, 129.0, 128.7, 128.6, 127.1, 16.4, 62.4, 61.8, 37.6, 14.0. HRMS (ESI

+

): m/z calcd for

C

19

H

19

N

3

O

2

[M+H]

+

: 322.1511, found 322.1547.

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Supporting Information

S17

8ac (32%)

Benzyl (S)-3-phenyl-2-(5-phenyl-1H-1,2,3-triazol-1-yl)propanoate: The procedure

described above was applied to acetophenone (50 mg, 0.42 mmol), benzyl

L

-phenylalaninate

(149 mg, 0.58 mmol), 4-nitrophenyl azide (76 mg, 0.46 mmol), 4 Å molecular sieves (50 mg)

and toluene (0.4 mL). The product was purified by flash column chromatography (CH

2

Cl

2

followed by petroleum ether /EtOAc = 8:2) affording 8ac (51.5 mg, 32% yield) as a yellow

solid m.p. 96 - 98 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.55 (s, 1H), 7.38 - 7.31 (m,4H), 7.27 -

7.22 (m, 4H), 7.18 - 7.12 (m, 3H), 6.87 - 6.84 (m, 2H), 6.69 - 6.67 (m , 2H), 5.20 (dd, J =

12.4, 29.2 Hz, 2H), 5.05 (dd, J = 4.1, 12.4, Hz, 1H), 3.77 (dd, J = 11.5, 14.1 Hz, 1H), 3.61

(dd, J = 4.2, 13.7 Hz, 1H).

13

C NMR (100 MHz, CDCl

3

) δ 167.7, 139.6, 135.9, 134.8, 132.4,

129.5, 129.1, 129.0, 128.8, 128.7, 128.61, 128.59, 128.5, 128.1, 127.1, 126.2, 67.8, 61.8,

37.4. HRMS (ESI

+

): m/z calcd for C

24

H

21

N

3

O

2

[M+H]

+

: 384.1667, found 384.1704.

8b (52%)

Tert-butyl (R)-3-phenyl-2-(5-(p-tolyl)-1H-1,2,3-triazol-1-yl)propanoate: The procedure

described above was applied to 4-methylacetophenone (50 mg, 0.37 mmol), tert-butyl

D

-

phenylalaninate (115.5 mg, 0.52), 4-nitrophenyl azide (67 mg, 0.41 mmol) 4Å molecular

sieves (50 mg) and toluene (0.4 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8b (71 mg, 52%

yield) as a yellow-red solid m.p. 82 - 84 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.53 (s, 2H), 7.21 –

7.14 (m, 3H), 7.12 (d, J = 7.8 Hz, 2H), 6.89 (d, J = 6.1 Hz, 2H), 6.65 (d, J = 7.8 Hz, 2H), 4.91

(dd, J = 11.3, 4.2 Hz, 1H), 3.78 – 3.68 (m, 1H), 3.55 (dd, J = 14.1, 4.1 Hz, 1H), 2.37 (s, 3H),

1.40 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 166.9, 139.6, 139.5, 136.4, 132.3, 129.4, 129.0,

129.0, 128.5, 126.9, 123.5, 83.2, 62.3, 37.3, 27.8, 21.3. HRMS (ESI

+

): m/z calcd for

C

22

H

25

N

3

O

2

[M+H]

+

: 364.1980; found 364.2016.

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Supporting Information

S18

8c (58%)

Tert-butyl (S)-2-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoate: The

procedure described above was applied to 4-methoxyacetophenone (50 mg, 0.33 mmol),

tert-butyl

L

-phenylalaninate (103 mg, 0.47), 4-nitrophenyl azide (60 mg, 0.37 mmol) 4 Å

molecular sieves (50 mg) and toluene (0.3 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8c (85 mg, 71%

yield) as a yellow-brown oil.

1

H NMR (400 MHz, CDCl

3

) δ 7.51 (s, 1H), 7.23 – 7.11 (m, 3H),

6.89 (d, J = 6.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 4.89 (dd, J = 11.4,

4.1 Hz, 1H), 3.82 (s, 3H), 3.77 – 3.67 (m, 1H), 3.54 (dd, J = 14.0, 4.1 Hz, 1H), 1.41 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 166.9, 160.5, 139.3, 136.4, 132.3, 130.5, 129.1, 128.5, 127.0,

118.5, 114.2, 83.2, 62.3, 55.3, 37.3, 27.8. HRMS (ESI

+

): m/z calcd for C

22

H

25

N

3

O

3

[M+H]

+

:

380.1929; found 380.1967.

8d (50%)

Tert-butyl (S)-2-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoate: The

procedure described above was applied to 3-fluoroacetophenone (50 mg, 0.36 mmol), tert-

butyl

L

-phenylalaninate (112 mg, 0.51), 4-nitrophenyl azide (65 mg, 0.40 mmol) 4 Å

molecular sieves (50 mg) and toluene (0.4 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8d (66 mg, 50%

yield) as a yellow solid m.p. 62 - 64 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.56 (s, 1H), 7.30 (dd, J

= 14.0, 7.6 Hz, 1H), 7.23 – 7.13 (m, 3H), 7.13 – 7.06 (m, 1H), 6.87 (d, J = 6.9 Hz, 2H), 6.58

(d, J = 7.6 Hz, 1H), 6.41 (d, J = 9.1 Hz, 1H), 4.88 (dd, J = 11.5, 4.0 Hz, 1H), 3.77 – 3.67 (m,

1H), 3.55 (dd, J = 14.1, 4.0 Hz, 1H), 1.42 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 166.6, 163.7,

161.2, 138.3, 138.3, 136.2, 132.4, 130.5, 130.4, 129.0, 128.6, 128.5, 128.5, 127.1, 124.9,

124.9, 83.5, 62.6, 37.3, 27.8. HRMS (ESI

+

): m/z calcd for C

21

H

22

FN

3

O

2

[M+H]

+

368.1730;

found 368.1764.

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Supporting Information

S19

8e (45%)

Tert-butyl (S)-2-(5-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoate: The

procedure described above was applied to 4-fluoroacetophenone (50 mg, 0.36 mmol), tert-

butyl

L

-phenylalaninate (112 mg, 0.51), 4-nitrophenyl azide (65 mg, 0.40 mmol) 4 Å

molecular sieves (50 mg) and toluene (0.4 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8e (60 mg, 45%

yield) as a yellow solid m.p. 87 - 89 ˚C

1

H NMR (400 MHz, CDCl

3

) δ 7.54 (s, 1H), 7.23 – 7.12

(m, 3H), 7.00 (t, J = 8.4 Hz, 2H), 6.86 (d, J = 6.9 Hz, 2H), 6.73 – 6.67 (m, 2H), 4.82 (dd, J =

11.5, 4.0 Hz, 1H), 3.77 – 3.67 (m, 1H), 3.53 (dd, J = 14.0, 3.9 Hz, 1H), 1.42 (s, 9H).

13

C NMR

(101 MHz, CDCl

3

) δ 166.7, 164.6, 162.1, 138.5, 136.4, 132.4, 131.2, 131.1, 129.0, 128.6,

127.0, 122.5, 122.5, 116.0, 115.8, 83.4, 62.5, 37.3, 27.8. HRMS (ESI

+

): m/z calcd for

C

21

H

22

FN

3

O

2

[M+H]

+

368.1730; found 368.1762.

8f (71%)

Tert-butyl (S)-2-(5-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoate: The

procedure described above was applied to 4-fluoroacetophenone (50 mg, 0.30 mmol), tert-

butyl L-phenylalaninate (94 mg, 0.42), 4-nitrophenyl azide (55 mg, 0.33 mmol) 4 Å molecular

sieves (50 mg) and toluene (0.3 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8f (85 mg, 71%

yield) as a yellow-brown oil.

1

H NMR (400 MHz, CDCl

3

) δ 8.17 (d, J = 8.5 Hz, 2H), 7.64 (s,

1H), 7.25 – 7.13 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 7.1 Hz, 2H), 4.81 (dd, J =

11.6, 3.8 Hz, 1H), 3.79 – 3.67 (m, 1H), 3.55 (dd, J = 14.1, 3.7 Hz, 1H), 1.44 (s, 9H).

13

C NMR

(101 MHz, CDCl

3

) δ 166.2, 148.4, 137.5, 136.2, 133.1, 132.8, 130.1, 129.0, 128.8, 127.3,

123.9, 83.8, 63.0, 37.4, 27.8. HRMS (ESI

+

): m/z calcd for C

21

H

22

N

4

O

4

[M+H]

+

: 395.1675;

found 395.1711.

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S20

8g (41%)

Tert-butyl (S)-2-(5-(1H-indol-3-yl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoate: The

procedure described above was applied to 3-acetylindole (50 mg, 0.31 mmol), tert-butyl L-

phenylalaninate (97 mg, 0.43), 4-nitrophenyl azide (57 mg, 0.34 mmol) 4 Å molecular sieves

(50 mg) and toluene (0.3 mL). The product was purified by flash column chromatography

(CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8g (50 mg, 41% yield) as an off

white solid. m.p. 155 - 156 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 8.92 (s, 1H), 7.68 (s, 1H), 7.44

(d, J = 8.2 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.21 – 7.05 (m, 5H), 6.88 (d, J = 6.9 Hz, 2H), 6.57 –

6.52 (m, 1H), 5.04 (dd, J = 11.2, 4.2 Hz, 1H), 3.79 – 3.69 (m, 1H), 3.56 (dd, J = 14.0, 4.2 Hz,

1H), 1.41 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 167.2, 136.6, 135.8, 133.4, 133.2, 129.2,

128.5, 126.9, 126.6, 124.7, 123.0, 120.8, 119.0, 111.5, 101.3, 83.2, 62.4, 37.6, 27.8. HRMS

(ESI

+

): m/z calcd for C

23

H

24

N

4

O

2

[M+H]

+

389.1933; found 389.1965.

8h (45%)

Tert-butyl (R)-2-(5-(naphthalen-1-yl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoate: The

procedure described above was applied to 1-acetonaphthone (50 mg, 0.29 mmol) tert-butyl

D

-phenylalaninate (91 mg, 0.41), 4-nitrophenyl azide (53 mg, 0.32 mmol) 4 Å molecular

sieves (50 mg) and toluene (0.3 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8h (53 mg, 45%

yield) as a yellow-brown oil.

1

H NMR (400 MHz, CDCl

3

) δ 7.94 – 7.83 (m, 2H), 7.65 (s, 1H),

7.60 – 7.33 (m, 3H), 7.26 – 7.04 (m, 4H), 6.93 – 6.73 (m, 2H), 5.84 (bs, 1H), 4.61 (bs, 1H),

3.90 – 3.60 (m, 1H), 3.49 (dd, J = 13.9, 3.7 Hz, 1H), 1.40 (s, 9H).

13

C NMR (100 MHz,

CDCl

3

) δ 166.9, 137.4, 136.4, 133.7, 133.2, 132.0, 130.2, 129.3, 128.8, 128.7, 128.6, 128.4,

128.2, 127.0, 126.4, 126.1, 125.9, 124.8, 113.4, 83.4, 62.6, 27.8. HRMS (ESI

+

): m/z calcd for

C

25

H

25

N

3

O

2

[M+H]

+

: 400.2010; found 400.2012.

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Supporting Information

S21

8i (69%)

Tert-butyl (R)-2-(5-(furan-2-yl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoate: The procedure

described above was applied to 2-acetylfuran (50 mg, 0.45 mmol), tert-butyl D-

phenylalaninate (111 mg, 0.64), 4-nitrophenyl azide (82 mg, 0.50 mmol) 4 Å molecular

sieves (50 mg) and toluene (0.4 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8i (106 mg,

69% yield) brown solid m.p. 63 - 65 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.77 (s, 1H), 7.51 (dd, J

= 1.8, 0.8 Hz, 1H), 7.20 – 7.14 (m, 3H), 7.11 – 7.06 (m, 2H), 6.49 (dd, J = 3.4, 1.8 Hz, 1H),

6.47 (dd, J = 3.5, 0.7 Hz, 1H), 5.53 (dd, J = 9.3, 6.1 Hz, 1H), 3.74 (d, J = 5.7 Hz, 1H), 3.71

(d, J = 2.4 Hz, 1H), 1.37 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 167.1, 143.7, 141.2, 136.4,

132.0, 129.7, 129.0, 128.5, 127.0, 111.7, 110.5, 83.3, 64.1, 36.9, 27.7. HRMS (ESI

+

): m/z

calcd for C

19

H

21

N

3

O

3

[M+H]

+

340.1616; found 340.1647

8j (12%)

Tert-butyl (R)-2-(5-(ferrocenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoate. The procedure

described above was applied to acetylferrocene (100 mg, 0.44 mmol) tert-butyl

D

-

phenylalaninate (136 mg, 0.61), 4-nitrophenyl azide (80 mg, 0.48 mmol) 4 Å molecular

sieves (50 mg) and toluene (0.4 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8j (24 mg, 12%

yield) as a dark yellow solid m.p. 123 - 125 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.63 (s, 1H),

7.23 – 7.16 (m, 3H), 7.05 – 6.97 (m, 2H), 5.17 (dd, J = 10.8, 4.4 Hz, 1H), 4.30 – 4.22 (m,

3H), 4.03 (s, 5H), 3.88 (d, J = 22.1 Hz, 1H), 3.79 (dd, J = 13.8, 11.1 Hz, 1H), 3.61 (dd, J =

14.1, 4.4 Hz, 1H), 1.41 (s, 9H).

13

C NMR (101 MHz, CDCl

3

) δ 167.1, 137.3, 136.6, 132.9,

129.2, 128.6, 127.0, 83.3, 70.8, 69.6, 69.4, 69.4, 68.9, 68.5, 62.6, 37.2, 27.8. HRMS (ESI

+

):

m/z calcd for C

25

H

27

FeN

3

O

2

[M+H]

+

: 458.1486; found 458.1516.

8k (20%)

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S22

Tert-butyl (R)-2-(5-butyl-4-propyl-1H-1,2,3-triazol-1-yl)-3-phenylpropanoate. The

procedure described above was applied to nonan-5-one (50 mg, 0.35 mmol), tert-butyl

L

-

phenylalaninate (108 mg, 0.49), 4-nitrophenyl azide (63.5 mg, 0.39 mmol) 4 Å molecular

sieves (50 mg) and toluene (0.3 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8k (26 mg, 20%

yield) as a yellow oil.

1

H NMR (400 MHz, CDCl

3

) δ 7.17 - 1.16 (m, 3H), 7.00 - 6.97 (m, 2H),

4.78 (dd, J = 4.3, 10.7 Hz, 1H), 3.75 - 3.70 (m, 1H), 3.58 (dd, J = 4.3, 13.9 Hz, 1H), 2.56 -

2.48 (m, 2H), 2.30 - 2.23 (m, 1H), 2.16 - 2.08 (m, 1H), 1.72 - 1.63 (m, 3H), 1.39 (s, 9H), 1.13

- 1.03 (m, 4H), 0.89 (t, J = 7.3 Hz, 3H), 0.78 (t, J = 6.6 Hz, 3H).

13

C NMR (100 MHz, CDCl

3

) δ

167.1, 144.0, 136.8, 134.2, 129.1, 128.5, 126.9, 83.0, 62.6, 37.3, 30.8, 27.8, 26.9, 22.8,

22.2, 21.7, 13.7, 13.6. HRMS (ESI

+

): m/z calcd for C

22

H

33

N

3

O

2

[M+H]

+

: 372.2606; found

372.2642.

8l (52%)

Tert-butyl (R)-3-phenyl-2-(5-(p-tolyl)-1H-1,2,3-triazol-1-yl)propanoate: The procedure

described above was applied to propiophenone (50 mg, 0.37 mmol), tert-butyl

D

-

phenylalaninate (115.5 mg, 0.52), 4-nitrophenyl azide (67 mg, 0.41 mmol) 4 Å molecular

sieves (50 mg) and toluene (0.4 mL). The product was purified by flash column

chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 7:3) affording 8l (71 mg, 52%

yield) as a yellow solid m.p. 58 - 60 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.53 (s, 2H), 7.21 –

7.14 (m, 3H), 7.12 (d, J = 7.8 Hz, 2H), 6.89 (d, J = 6.1 Hz, 2H), 6.65 (d, J = 7.8 Hz, 2H), 4.91

(dd, J = 11.3, 4.2 Hz, 1H), 3.78 – 3.68 (m, 1H), 3.55 (dd, J = 14.1, 4.1 Hz, 1H), 2.37 (s, 3H),

1.40 (s, 9H).

13

C NMR (100 MHz, CDCl

3

) δ 166.9, 139.6, 139.5, 136.4, 132.3, 129.4, 129.1,

129.0, 128.5, 127.0, 123.5, 83.2, 62.3, 37.3, 27.8, 21.3. HRMS (ESI

+

): m/z calcd for

C

22

H

25

N

3

O

2

[M+H]

+

: 364.1980; found 364.2016.

8m (95%)

Tert-butyl 2- (5-phenyl-1H-1,2,3-triazol-1-yl)acetate: Acetophenone (52 mg, 0.42 mmol),

tert-butyl glycinate (77 mg, 0.58 mmol), 4-nitrophenyl azide (75 mg, 0.46 mmol), 4Å

molecular sieves (50 mg) and toluene (0.4 mL) were mixed in a sealed reaction tube 24

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S23

hours at 100 °C. After the solvent was removed under reduced pressure and the crude

reaction mixture was purified by flash column chromatography (CH

2

Cl

2

followed by

heptane/EtOAc = 6:4) affording 8m (106 mg, 95% yield) as an off white semi solid.

1

H NMR

(300 MHz, CDCl

3

) δ 7.75 (s, 1H), 7.49 - 7.47 (m, 3H), 7.41 - 7.37 (m, 2H), 5.04 (s, 1H), 1.39

(s, 9H).

13

C NMR (75 MHz, CDCl

3

) δ 165.6, 138.7, 133.0, 129.8, 129.2, 128.7, 126.9, 83.6,

50.3, 27.9; HRMS (ESI

+

): m/z calcd for C

14

H

18

N

3

O

2

[M+H]

+

: 260.1393, found 260.1392.

8n (71%)

Tert-butyl (2S,3S)-3-methyl-2-(5-phenyl-1H-1,2,3-triazol-1-yl)pentanoate: The procedure

described above was applied to acetophenone (50 mg, 0.42 mmol), tert-butyl

L

-isoleucinate

(109 mg, 0.58 mmol), 4-nitrophenyl azide (75 mg, 0.46 mmol), 4Å molecular sieves (50 mg)

and toluene (0.4 mL). The product was purified by flash column chromatography (CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2) affording 8n (93 mg, 71% yield) as a yellow oil.

1

H

NMR (400 MHz, CDCl

3

) δ 7.70 (s, 1H), 7.53 – 7.47 (m, 3H), 7.42 – 7.36 (m, 2H), 4.59 (d, J =

9.0 Hz, 1H), 2.77 – 2.68 (m, 1H), 1.44 (s, 9H), 1.28 – 1.17 (m, 1H), 1.09 – 0.96 (m, 4H), 0.77

(t, J = 7.4 Hz, 3H).

13

C NMR (100 MHz, CDCl

3

) δ 167.15, 139.20, 132.49, 129.64, 129.31,

129.07, 126.98, 82.92, 66.07, 36.62, 27.85, 25.45, 15.85, 10.81. HRMS (ESI

+

): m/z calcd for

C

18

H

25

N

3

O

2

[M+H]

+

: 316.1980; found 316.2021.

8o (64%)

Tert-butyl (S)-3-(4-hydroxyphenyl)-2-(5-phenyl-1H-1,2,3-triazol-1-yl)propanoate: The

procedure described above was applied to acetophenone (50 mg, 0.42 mmol),

L

-tyrosine

tert-butyl ester (138 mg, 0.58), 4-nitrophenyl azide (75 mg, 0.46 mmol) 4Å molecular sieves

(50 mg) and toluene (0.4 mL). The product was purified by flash column chromatography

(CH

2

Cl

2

followed by petroleum ether/EtOAc = 8:2) affording 8o (96 mg, 63% yield as a

yellow solid m.p. 140 - 142 ˚C.

1

H NMR (400 MHz, CDCl

3

) δ 7.55 (s, 1H), 7.47 – 7.31 (m,

3H), 6.87 (d, J = 7.4 Hz, 2H), 6.80 – 6.73 (m, 2H), 6.71 – 6.63 (m, 2H), 4.98 – 4.90 (m, 1H),

3.74 – 3.63 (m, 1H), 3.51 – 3.43 (m, 1H), 1.41 (s, 9H).

13

C NMR (101 MHz, CDCl

3

) δ 166.9,

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Supporting Information

S24

155.7, 139.8, 132.1, 130.1, 130.1, 129.7, 129.2, 128.8, 127.2, 126.3, 115.6, 83.4, 62.8, 36.3,

27.8. HRMS (ESI

+

): m/z calcd for C

21

H

23

N

3

O

3

[M+H]

+

: 366.1773; found 366.1808

7.

1

H and

13

C NMR spectra for compound of 5a-p

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Supporting Information

S25

Figure S3.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5a.

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Supporting Information

S26

Figure S4.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5l.

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Supporting Information

S27

Figure S5.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5ab

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Supporting Information

S28

Figure S5.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5ac

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Supporting Information

S29

Figure S6.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5ad

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Supporting Information

S30

Figure S7.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5b.

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Supporting Information

S31

Figure S8.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5c.

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Supporting Information

S32

Figure S9.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5d.

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Supporting Information

S33

Figure S10.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5e

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Supporting Information

S34

Figure S11.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5f.

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Supporting Information

S35

Figure S12.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5g.

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Supporting Information

S36

Figure S13.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5h.

HN

O

MeO

O

Ph

N

5h

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Supporting Information

S37

Figure S14.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5i.

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Supporting Information

S38

Figure S15.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5j.

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Supporting Information

S39

Figure S16.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5k.

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Supporting Information

S40

Figure S17.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5m.

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Supporting Information

S41

Figure S18.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5n.

5n

H

OH

N

CO2t-Bu

Ph

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Supporting Information

S42

Figure S19.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5o.

H

OH

N

CO2t-Bu

Ph

5o

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Supporting Information

S43

Figure S20.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 5p.

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Supporting Information

S44

8.

1

H and

13

C NMR spectra for compound 8a-o

Figure S21.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8a

.

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Supporting Information

S45

Figure S22.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8aa

.

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S46

Figure S23.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8ab

.

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Supporting Information

S47

Figure S24.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8ac

.

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Supporting Information

S48

Figure S25.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8b

.

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Supporting Information

S49

Figure S26.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8c

.

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Supporting Information

S50

Figure S27.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8d

.

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S51

Figure S28.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8e

.

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S52

Figure S29.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8f

.

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S53

Figure S30.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8g

.

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S54

Figure S31.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8h.

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S55

Figure S32.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8i.

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S56

Figure S33.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8j.

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S57

Figure S34.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8k.

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S58

Figure S35.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 8l.

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S59

Figure S36.

1

H-NMR (300 MHz, CDCl

3

) and

13

C NMR (75 MHz, CDCl

3

) Spectra of 8m.

165.6397

138.7421

133.0331

129.7739

129.2197

128.7458

126.8792

83.6420

77.4808

77.1600

76.8465

50.2625

27.9074

(ppm)

0102030405060708090100110120130140150160170

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S60

Figure S37.

1

H-NMR (300 MHz, CDCl

3

) and

13

C NMR (75 MHz, CDCl

3

) Spectra of 8n.

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S61

Figure S38.

1

H-NMR (300 MHz, CDCl

3

) and

13

C NMR (75 MHz, CDCl

3

) Spectra of 8o.

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S62

9. Synthesis procedure of 9a

Figure S39. Carboxylic acid derivative obtained from acid hydrolysis.

a

Determined by

1

H-

NMR spectroscopy, no side products were observed.

b

d.r. determined by

1

H-NMR analysis

of the crude product 9a.

(S)-2-((1R,3aS,3bR,5aS,10aS,10bS,12aR)-10a,12a-dimethyl-1-((R)-4-methylpentan-2-yl)-

2,3,3a,3b,4,5,5a,6,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[7,8]phenanthro[2,3-

d][1,2,3]triazol-7(1H)-yl)-3-phenylpropanoic acid : 5a (20 mg, 0.03 mmol) was dissolved

in 1,4-dioxane (1.0 mL), then 0.5 mL of 6M HCl (aq) was added at R.T. and the reaction was

stirred 5h at 85 °C. After, the mixture was cooled to R.T. and water and ether were added.

The mixture was then separated and the aqueous layer was extracted with ether 3 times.

The combined organic fractions were recollected and dried over MgSO

4

, filtered and the

solvent was removed under reduced pressure affording a mixture of 9a and tert-butanol

(100% conversion).

1

H NMR (400 MHz, CDCl

3

) δ 7.20 – 7.19 (m, 3H), 6.93 (m, 2H), 5.03

(dd, J = 3.4, 11.5 Hz, 1H), 3.65 (dd, J = 3.7, 13.7 Hz, 1H), 3.56 – 3.51 (m, 1H), 2.78 (d, J =

15.6 Hz, 1H), 2.22 – 2.17 (m, 2H), 2.05 – 2.03 (m, 2H), 1.87 – 1.84 (m, 2H), 1.67 – 1.66 (m,

2H), 1.56 – 1.51 (m, 4H), 1.41 – 1.32 (m, 7H), 1.20 – 1.09 (m, 5H), 1.06 – 0.98 (m, 4H), 0.94

– 0.88 (m, 11H), 0.67 (s, 3H), 0.38 (s, 1H).

13

C NMR (100 MHz, CDCl

3

) δ 169.1, 143.0,

135.8, 133.0, 128.9, 128.8, 127.3, 62.8, 56.2, 56.1, 53.4, 42.4, 41.7, 39.8, 39.5, 39.07, 36.7,

36.2, 35.8, 35.6, 35.4, 31.4, 29.7, 28.8, 28.2, 28.0, 24.2, 23.8, 22.8, 22.6, 21.1, 18.7, 14.1,

11.9, 11.3. HRMS (ESI

+

): m/z calcd for C

36

H

53

N

3

O

2

[M+H]

+

560.4171; found 560.4192.

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S63

10.

1

H and

13

C NMR spectra for compound 9a and rac-9a

Figure S39.

1

H-NMR (400 MHz, CDCl

3

) and

13

C NMR (100 MHz, CDCl

3

) Spectra of 9a

(mixture tert-butanol 9a).

tert-butanol

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S64

Figure S40.

1

H-NMR comparison between 9a, rac-9a and 5a.

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